The generation of induced pluripotent stem cells (iPSCs) through the use of small molecule compounds has evolved as a potential cellular reprogramming strategy. Individually, specific small molecule compounds have previously been shown to replace reprogramming transcription factors or enhance the efficiency of cellular reprogramming. More recently, a combination of small molecule compounds can replace all of the reprogramming factors. In this review, we describe in detail the generation of chemically induced pluripotent stem cells using small molecule inhibitors and activators that target either downstream protein kinases or modify chromatin structure to promote somatic cell reprogramming. In addition, epigenetic modulating small molecule compounds that enhance cellular reprogramming and functionally replace some reprogramming factors are discussed.
Streamline the management of your screening compounds with our Aldrich Market Select online order center for small molecule libraries, comprising over 14 million chemistry building blocks and other useful services.
The selection, acquisition, and use of high‐quality small molecule libraries for screening is an essential aspect of drug discovery and chemical biology programs
Hepatitis C virus (HCV) poses a major health threat to the world. The recent development of direct-acting antivirals (DAAs) against HCV has markedly improved the response rate of HCV and reduced the side effects in comparison to the interferon-based therapy. Despite this therapeutic advance, there is still a need to develop new inhibitors that target different stages of the HCV life cycle because of various limitations of the current regimens. In this study, we performed a quantitative high throughput screening of the Molecular Libraries Small Molecule Repository (MLSMR) of ∼350,000 chemicals for novel HCV inhibitors using our previously developed cell-based HCV infection assay. Following confirmation and structural clustering analysis, we narrowed down to 158 compounds from the initial ∼3000 molecules that showed inhibitory activity for further structural and functional analyses. We were able to assign the majority of these compounds to specific stage(s) in the HCV life cycle. Three of them ...
A select offering of Pharma-Developed bioactive small molecules, both approved therapeutics/drug candidates and tool compounds, is tailored for potential use in Late Stage Functionalization. The compounds selected can be modified to include fluorine, which, despite appearing sparingly in naturally-occurring compounds, is found in fully 25% of FDA approved drugs.Solutions to incorporate fluorine into your Lead compound are explored further in our Fluorination Application Guide.Specifically, phenolic and alkyl carbinols can be converted directly to fluorine using PhenoFluor™, a late-stage deoxyfluorination reagent.
Bioisosteric replacement and scaffold hopping are twin methods used in drug design to improve the synthetic accessibility, potency and drug like properties of a compound and to move into novel chemical space. Bioisosteric replacement involves swapping functional groups of a molecule with other functional groups that have similar biological properties. Scaffold hopping is the replacement of the core framework of a molecule with another scaffold that will improve the properties of the molecule or to find similar potent compounds that exist in novel chemical space. This review outlines the key concepts, importance and challenges of both methods using examples and comparisons of techniques available for finding bioisosteric replacements and scaffold hops. There are many methods available for bioisosteric replacement and scaffold hopping, all with their own advantages and disadvantages. Drug design projects would benefit from a combination of these methods to retrieve diverse and complimentary ...
Emerald BioStructures (formerly deCODE biostructures) announced a publication in the December 27, 2009 advance online issue of Nature Biotechnology, detailing the application of structure-based drug design (SBDD) to engineer ...
Small-molecule microarrays composed of tens of thousands of distinct synthetic molecules, natural products, and their combinations/modifications provide a high-throughput platform for studying protein-ligand interactions. Immobilization of small molecule compounds on solid supports remains a challenge as widely varied small molecules generally lack unique chemical groups that readily react with singly or even multiply functionalized solid support. We explored two strategies for immobilizing small molecule compounds on epoxy-functionalized glass surface using primary-aminecontaining macromolecular scaffolds: bovine serum albumin (BSA) and amine-modified poly-vinyl alcohol (PVA). Small molecules with N-hydroxysuccinimide (NHS) groups were conjugated to BSA or amine-modified PVA. Small-molecule-BSA conjugates and small-molecule-PVA conjugates were subsequently immobilized on epoxy-functionalized glass slides through amine-epoxy reactions. Using an oblique-incidence reflectivity difference (OI-RD) ...
Many hematopoietic and nonhematopoietic diseases require chemotherapy and radiotherapy for treatment. Unfortunately, these regimens induce long-term damage, deleterious side effects and require multiple treatments for success. Hematopoietic stem cell (HSC) transplantation has proven effective in treatments but requires HLA-matching of these products to prevent complications, a process not easily achieved. Umbilical cord blood has become a standard in therapeutic transplantation primarily due to the ability to avoid more stringent HLA-matching. However, the low stem cell numbers in cord blood which limits use primarily in pediatric patients requires ex vivo expansion to increase patient availability. Clinical expansion is difficult to achieve and costly necessitating the need for enhanced protocols. The recent identification of inducing pluripotency by small molecule compounds has become an attractive option in HSC expansion. Our aim was to identify compounds that could induce self-renewal ...
Staphylococcus aureus quickly develops resistance to antibiotics and poses a significant health threat to humans. New antibiotic targets are needed for the development of new antibiotics. Trans-translation has important roles in maintaining bacterial viability. Small molecules, KKL-35 and KKL-40, were recently identified as specific inhibitors of trans-translation. We have investigated the roles of trans-translation on S. aureus viability and the potential of KKL-35 and KKL-40 as antibiotics. We find that KKLs show bactericidal activity against multiple S. aureus strains at relatively low concentration. We also find that sub-lethal doses of KKLs make S. aureus more susceptible to antimicrobials. Neither KKL-35 nor KKL-40 are cytotoxic to human HeLa cells. Unfortunately, KKL-40 is inactivated by human serum. Therefore, new inhibitors will need to be identified in future studies. Notably, the development of resistance by S.aureus against KKLs remains at a low level. Therefore trans-translation is ...
Scientists at the University of Duesseldorf and the University of Erlangen have developed new small molecules which can be used for the treatment of diseases characterized by the presence of misfolded proteins. Examples for such medical conditions are prion diseases, e.g. CJD, as well as neurodegenerative (e.g. Alzheimers disease) or neuropsychiatric diseases. Compo-Q have a structural relationship to quinacrine which is considered to be one of the most promising candidate for the clinical therapy of prion diseases. In Compo-Q the modified quinacrine is covalently linked to a derivative of another substance which has been proven effective against prion diseases in vitro ...
Scientists at the University of Bonn have identified new small molecules which can be used for the treatment of diseases characterized by alterations of proteins which are affected by Guanine nucleotide Exchange Factors (GEFs). Proteins targeted by GEFs are involved in integrin signalling, vesicle transport, or MAPK-signalling. These processes play an important role in the modulation of the immune response. Therefore, abnormal activation of the target proteins of GEFs can cause autoimmune and tumor diseases in humans ...
Deubiquitinases (DUBs) have been proposed as therapeutic targets in cancer due to their ability to alter degradation rates of known oncoproteins. However, previous efforts to develop potent and selective DUB inhibitors have been largely unsuccessful. In this work, we develop a target class drug discovery platform targeting DUBs, which incorporates small molecule libraries, enzyme libraries, and a suite of structural and functional activity assays. Using this platform, we demonstrate one of the first examples of potent and selective DUB inhibitor development, targeting USP7 (chapter II). We then use our potent USP7 inhibitors (chapter III) as well as our annotated DUB-wide small molecule library (chapter IV) in a series of cellular assays to identify novel biological function of USP7 (chapter III) and USP10 (chapter IV). Finally, we describe our efforts to improve and expand our current target class library in order to continue to identify novel DUB inhibitors and DUB biology. ...
Walczak M, Ganesan SM, Niles JC, Yeh E. (2017) ATG8 is essential specifically for an autophagy-independent function in apicoplast biogenesis in blood-stage malaria parasites. mBio (In press). Gisselberg JE, Herrera Z, Altenhofen L, Llinas M, Yeh E. (2017) Specific inhibition of the bifunctional farnesyl/geranylgeranyl diphosphate synthase in malaria parasites via a new small molecule binding site. Cell Chemical Biology (In press) (Preprint) Amberg-Johnson K, Hari SB, Ganesan SM, Lorenzi HA, Sauer RT, Niles JC, Yeh E. (2017) Small molecule inhibition of apicomplexan FtsH1 disrupts plastid biogenesis in human pathogens. eLife. doi: 10.7554/eLife.29865 (PubMed) (PDF). Gisselberg JE, Zhang L, Elias JE, and Yeh E. The prenylated proteome of Plasmodium reveals pathogen-specific prenylation. Mol Cell Proteomics. 2016 Dec. doi: 10.1074/mcp.M116.064550. (PubMed) (PDF). Wu W, Herrera Z, Ebert D, Baska K, DeRisi JL, Yeh E (2014) A chemical rescue screen identifies a Plasmodium falciparum apicoplast ...
Hello, I am applying for a PhD position in Chemistry and my motivation letter need to be checked. Thank you Dear Mr., I am an undergraduate student and as my CV indicates in June of this year I expect to receive B. Sc. degree in Chemistry and in 2015 M. Sc. degree. In future, I see myself only as a researcher, so after graduation I want to continue my education as a PhD student. On my part your projects devoted to synthesis of new small molecule modulators and synthetic approach to
Replication stress is a common feature of cancer cells. Ataxia telangiectasia-mutated (ATM) and Rad3-related (ATR) signalling, a DNA damage repair (DDR) pathway, is activated by regions of single-stranded DNA (ssDNA) that can arise during replication stress. ATR delays cell cycle progression and prevents DNA replication fork collapse, which prohibits cell death and promotes proliferation. Several ATR inhibitors have been developed in order to restrain this protective mechanism in tumours. It is known, however, that despite other effective anticancer chemotherapy treatments targeting DDR pathways, resistance occurs. This begets the need to identify combination treatments to overcome resistance and prevent tumour cell growth. We conducted a drug screen to identify potential synergistic combination treatments by screening an ATR inhibitor (VE822) together with compounds from a bioactive small molecule library. The screen identified adefovir dipivoxil, a reverse transcriptase inhibitor and nucleoside
BioAssay record AID 686955 submitted by ICCB-Longwood/NSRB Screening Facility, Harvard Medical School: A confirmatory screen for small compounds that change glucocorticoid sensitivity in NFkB suppression.
A unique collection of 254 small molecule modulators with biological activity used for epigenetics research and associated assays. • The library contains epigenetics-related compounds targeting HDAC, Histone Demethylase, Histone Acetyltransferase (HAT), DNA Methyltransferase (DNMT), Epigenetic Reader Domain, MicroRNA, etc. • A valuable tool for chemical genomics, epigenetic target identification in pharmacogenomics, and other biological applications. • Bioactivity and safety confirmed by preclinical research and clinical trials. Some compounds have been approved by FDA.. • Structurally diverse, medicinally active, and cell permeable.. • Rich documentation with structure, IC50, and other chemical & biological data. • NMR and HPLC validated to ensure the highest purity. • All compounds are in stock and continuously updated. ...
The NIH Molecular Libraries Program (MLP) was founded to translate the discoveries of the Human Genome Project into therapeutics through a network of high-throughput screening (HTS) centers. A decade of discovery produced hundreds of probes - highly selective small molecules that modulate cellular function - but centralized compound screening bears the same cost and infrastructure burdens of millennial DNA sequencing centers, which has limited access to the technology and, more significantly, the rate of small molecule discovery. We are building a next-generation distributable drug discovery platform analogous to next-generation DNA sequencing. We have developed DNA-encoded solid-phase synthesis strategies to produce ultra-miniaturized compound libraries where each microscopic bead displays many copies of a small molecule library member and a corresponding amplifiable DNA that that encodes the structure. In parallel, we engineered microfluidic instrumentation for miniaturizing automated ...
3261 Genetic instability can lead to tumorigenesis, creating the need for cells to develop mechanisms and checkpoints to ensure faithful replication and division of genetic material. These mechanisms and checkpoints remain intact in normal cells, but are often disrupted or lost in cancer cells. Aurora kinases have mitotic regulatory functions and are important proteins in the maintenance of genetic stability, especially during mitosis. Aurora A localizes to the centrosomes during mitosis and is required for spindle assembly; atypical amounts of Aurora A in cells cause abnormal spindle formation and disruption of the spindle-assembly checkpoint. Overexpression of Aurora has been observed in several types of human cancers including breast, colorectal, prostate, ovarian, and pancreas. Aurora A represents a logical target because of its implication in tumorigenesis and, being a kinase, lends itself to small molecule inhibition. We have developed new small molecule inhibitors, the MP529 series, which ...
1a (4015344), 1b (9195793), 1c (4004590), 1d (4029846), 1e (9195764), 1f (5118322), 1g (4004588), 3a (4004567), 4a (9199706), 4b (5302581), 4c (4014290), 4d (9036489), 4e (4027111), 4f (4012916)4g (6044848), 5a (7356387), 6a (4001635), 6b (4011498), 7a (5310735), 8a (4012182), 8b (4004729), 9a (5140897), 10a (5314457), 11a (9192288), 11b (9248058), 12 (7964065), 13 (5141588), 14 (7117827), 15 (5107312 ...
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In a differential cytotoxicity screen, we identified a novel small molecule modulator of phosphodiesterase 3A (PDE3A) that kills cancer cells expressing elevated levels of PDE3A and SLFN12 (de Waal, Nat Chem Biol, 2016). Treatment with this cell-selective cytotoxic small molecule, DNMDP, induces complex formation between PDE3A and SLFN12, resulting in apoptosis. Inhibition of PDE3A enzymatic activity is not sufficient for cancer cell killing, and expression of both PDE3A and SLFN12 are required. Although the mechanism of signaling to the apoptosis machinery remains unclear, we examined more closely the role of the PDE3A-SLFN12 complex in cancer cell killing mediated by DNMDP. We found that cancer cell lines made resistant to DNMDP by persistent exposure downregulated SLFN12 expression and that re-expression of SLFN12 was sufficient to restore sensitivity. Furthermore, ectopic expression of PDE3A and SLFN12 are sufficient to sensitize cancer cells to DNMDP. These data underscore the tight ...
DNA-encoded chemical libraries (DEL) is a technology for the synthesis and screening on unprecedented scale of collections of small molecule compounds. DEL is used in medicinal chemistry to bridge the fields of combinatorial chemistry and molecular biology. The aim of DEL technology is to accelerate the drug discovery process and in particular early phase discovery activities such as target validation and hit identification. DEL technology involves the conjugation of chemical compounds or building blocks to short DNA fragments that serve as identification bar codes and in some cases also direct and control the chemical synthesis. The technique enables the mass creation and interrogation of libraries via affinity selection, typically on an immobilized protein target. A homogeneous method for screening DNA-encoded libraries has recently been developed which uses water-in-oil emulsion technology to isolate, count and identify individual ligand-target complexes in a single-tube approach. In contrast ...
Small molecules offer exciting opportunities for plant science. So far, bioactive small molecules have been identified as plant hormones, herbicides, growth regulators, or taken from animal research. Recently, plant scientists have started to explore further the chemical space for novel modulators of plant hormone signalling, and have followed up this work with exciting discoveries illustrating the potential of small molecules such as brassinazole and sirtinol. New chemical genetic screens have been designed to generate chemical tools for the investigation of membrane trafficking, gravitropism and plant immunity. Further novel chemetic tools to identify targets and modes of action are currently generated through an intimate interdisciplinary collaboration between biologists and small molecule chemists.
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In addition, many E3s have been implicated in human disease and are attractive targets for drug discovery. However, currently no small molecule modulators for this class of enzymes have reached the clinic. Each E3 enzyme targets a small number of proteins for Ub modification but the exact substrates are mostly unknown and their identification continues to be a challenge. E3 ligase enzymes are a large (> 500) and complex super- family, many of which contain binding domains to interact with ubiquitin, E2 enzymes and substrate proteins. In addition to substrate ubiquitination, many E3 ligases can also self- or auto-ubiquitinate in the presence of an E2 enzyme, a property that may be used as an auto-regulatory mechanism to control its own intracellular levels. In general, the detailed molecular mechanism, stoichiometries and linkage site selection of E3 enzymes are poorly understood. As with ubiquitin E3 ligases, similar activities are also part of the final conjugation processes for other UBL ...
Vasoactive intestinal peptide (VIP) is a neuroendocrine peptide that has been implicated in a myriad of functions. VIP promotes neuronal survival during development and apoptotic challenges. Further, VIP has been shown to regulate hormonal release, circadian rhythms, vasodilation, and T cell proliferation in central and peripheral tissues. VIP binds with equally high affinity to VPAC1 and VPAC2 receptors, members of the Class B family of G protein-coupled receptors (GPCRs) that also include the PAC1, glucagon (GCGR), and CRH receptors. VIP binding has previously been shown to increase downstream MAPK signaling cascades, especially MEK/ERK. Given the structural similarities and functional overlap between VPAC1 and VPAC2 receptors, we sought to investigate whether there are small molecule modulators that can probe and identify the functional distinctions between the two receptor subtypes. For these studies, we used HEK-293 cells stably expressing the VPAC1-EGFP or the VPAC2-EGFP receptor. The cultures
Dr. Eric Gross is an anesthesiologist developing non-narcotic cardiac-safe pain therapeutics. The Gross Lab is designing next generation analgesics that are safe to use for those with cardiovascular disease. Dr. Grosss previous basic science research background involves examining the mechanism of how opioids and volatile anesthetics protect tissue from ischemia-reperfusion injury and what are the molecular mechanisms involved both through in vivo and cellular models of ischemia-reperfusion injury. Dr. Che-Hong Chen is a molecular biologist and geneticist at the Stanford University School of Medicine. Dr. Chens research is highlighted by the discovery of a class of novel enzyme modulators of aldehyde dehydrogenase. Some of these small molecule modulators are potent enzyme activators for the variant East Asian-specific dysfunctional ALDH2, which causes the alcohol flushing syndrome. Dr. Chen is now actively promoting public health education, cancer prevention and the awareness of health risks ...
Sandhya Kortagere, PhD, is an associate professor in the Department of Microbiology & Immunology at Drexel University College of Medicine. She is interested in designing and developing small molecule modulators to treat neurodegenerative diseases.
Active efflux of antibiotics preventing their accumulation to toxic intracellular concentrations contributes to clinically relevant multidrug resistance. Inhibition of active efflux potentiates antibiotic activity, indicating that efflux inhibitors could be used in combination with antibiotics to reverse drug resistance. Expression of ramA by Salmonella enterica serovar Typhimurium increases in response to efflux inhibition, irrespective of the mode of inhibition. We hypothesized that measuring ramA promoter activity could act as a reporter of efflux inhibition. A rapid, inexpensive, and high-throughput green fluorescent protein (GFP) screen to identify efflux inhibitors was developed, validated, and implemented. Two chemical compound libraries were screened for compounds that increased GFP production. Fifty of the compounds in the 1,200-compound Prestwick chemical library were identified as potential efflux inhibitors, including the previously characterized efflux inhibitors mefloquine and ...
Research in the Hong group focuses on using chemical tools, in particular small molecules, to understand the signaling pathways in biology. We synthesize biologically interesting natural products and screen small molecule libraries to identify modulators of biological processes. Then, we explore their modes of action in order to investigate intracellular signaling pathways and identify novel targets for drug design. In addition, we design and develop unique and efficient synthetic strategies that will allow rapid access to molecular complexity and structural diversity. Through multidisciplinary approaches, including organic synthesis, molecular biology, and cell biology, the cellular components and molecular events that embody cancer, immune response, and GPCR signaling have systematically been explored. Compounds employed in these studies could also advance the development of novel therapeutics for the treatment of human diseases. ...
Research in the Hong group focuses on using chemical tools, in particular small molecules, to understand the signaling pathways in biology. We synthesize biologically interesting natural products and screen small molecule libraries to identify modulators of biological processes. Then, we explore their modes of action in order to investigate intracellular signaling pathways and identify novel targets for drug design. In addition, we design and develop unique and efficient synthetic strategies that will allow rapid access to molecular complexity and structural diversity. Through multidisciplinary approaches, including organic synthesis, molecular biology, and cell biology, the cellular components and molecular events that embody cancer, immune response, and GPCR signaling have systematically been explored. Compounds employed in these studies could also advance the development of novel therapeutics for the treatment of human diseases. ...
Atomwise announced the launch of a ten billion compound AI-powered virtual drug screening initiative, the 10-to-the-10 program, in collaboration with Enamine, the worlds largest chemical supplier. The initiative aims to dramatically increase the discovery of safer small molecule drugs to treat pediatric cancers.. Atomwise will use its patented AI virtual screening technology to evaluate the binding of billions of drug-like molecules to cancer target proteins, and Enamine will provide support and access to a virtual library of ten billion small molecule compounds. The research will be directed by the needs of innovators in cancer research at leading universities.. Cancer is diagnosed in more than 15,000 children and adolescents each year. Many cancers do not have effective treatments and for those that do, it is estimated that 80% have serious adverse effects that impact long-term health. Therefore, new oncology drugs are needed. The 10-to-the-10 program will search for novel drug candidates by ...
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Our data clearly demonstrate significant cardioprotective activities of the novel small molecule C1 inhibitor (C1s-INH-248) in myocardial ischemia and reperfusion. The cardioprotection exerted by C1s-INH-248 was characterized by a reduction of necrosis and decreased serum CK activity compared with rabbits given the vehicle only. The cardioprotective effect of C1s-INH-248 was dose dependent when administrated as a 0.1-1 mg/kg body weight bolus injection. Even compared with the treatment with the C1 esterase inhibitor (C1-INH) C1s-INH-248 demonstrated superior potency. The protection of C1s-INH-248 also resulted in inhibition of PMN accumulation in the reperfused myocardium. Further, the protective effect could be attributed to decreased deposition of C5b-9 on ischemic reperfused myocardium or vascular endothelial cells. To our knowledge, this is the first study demonstrating cardioprotection with a highly specific synthetic C1 inhibitor following myocardial ischemia and reperfusion.. To date, ...
TY - ABST. T1 - Chemical tools for unraveling the substrate specificity of the lysine deacylase enzymes. AU - Madsen, Andreas Stahl. AU - Olsen, Christian Adam. N1 - Tuesday, August 12, 2014 05:30 PM Current Topics in Biological Chemistry (05:30 PM - 08:00 PM) Location: San Francisco Marriott Marquis Room: Golden Gate Section A/B. PY - 2014. Y1 - 2014. N2 - The lysine deacylase (KDAC) enzymes catalyze hydrolytic removal of acyl functionalities from theε-amino group of lysine residues ina variety of proteins including histones, and KDAC-mediated deacetylation of proteins has been established as a key epigeneticandmetabolic regulator. Recent studies have highlighted lysine acetylation as a general post-translational modification (PTM), andagrowing list of non-histone proteins has been identified as substrates for the KDACs, thereby extending their potential impactoncellular function. Furthermore, other acyl groups (e.g., crotonyl, malonyl, succinyl, glutaryl, myristoyl and 3-phosphoglyceroyl) ...
Video articles in JoVE about high content screening include Ordering Single Cells and Single Embryos in 3D Confinement: A New Device for High Content Screening, A Microscopic Phenotypic Assay for the Quantification of Intracellular Mycobacteria Adapted for High-throughput/High-content Screening, High Content Screening Analysis to Evaluate the Toxicological Effects of Harmful and Potentially Harmful Constituents (HPHC), Generation and Multi-phenotypic High-content Screening of Coxiella burnetii Transposon Mutants, High Content Screening in Neurodegenerative Diseases, High Content Screeningはゆゆェソトリゲェトは祥絍紬胧は毐怣ェトソェ - ADVERTISEMENT, A Manual Small Molecule Screen Approaching High-throughput Using Zebrafish Embryos, A Fluorescence-based Lymphocyte Assay Suitable for High-throughput Screening of Small Molecules, A High-content In Vitro Pancreatic Islet β-cell Replication Discovery Platform, 3D Microtissues for Injectable Regenerative Therapy and
The Stivers Lab is broadly interested in the biology of the RNA base uracil when it is present in DNA. Our work involves structural and biophysical studies of uracil recognition by DNA repair enzymes, the central role of uracil in adapative and innate immunity, and the function of uracil in antifolate and fluoropyrimidine chemotherapy. We use a wide breadth of structural, chemical, genetic and biophysical approaches that provide a fundamental understanding of molecular function. Our long-range goal is to use this understanding to design novel small molecules that alter biological pathways within a cellular environment. One approach we are developing is the high-throughput synthesis and screening of small molecule libraries directed at important targets in cancer and HIV-1 pathogenesis.. Research Areas: biophysics, enzymes, cell biology, uracil, cancer, HIV, DNA, RNA ...
The Hedgehog (Hh) signaling pathway is vital to animal development as it mediates the differentiation of multiple cell types during embryogenesis. In adults, Hh signaling can be activated to facilitate tissue maintenance and repair. Moreover, stimulation of the Hh pathway has shown therapeutic efficacy in models of neuropathy. The underlying mechanisms of Hh signal transduction remain obscure, however: little is known about the communication between the pathway suppressor Patched (Ptc), a multipass transmembrane protein that directly binds Hh, and the pathway activator Smoothened (Smo), a protein that is related to G-protein-coupled receptors and is capable of constitutive activation in the absence of Ptc. We have identified and characterized a synthetic non-peptidyl small molecule, Hh-Ag, that acts as an agonist of the Hh pathway. This Hh agonist promotes cell-type-specific proliferation and concentration-dependent differentiation in vitro, while in utero it rescues aspects of the Hh-signaling defect
This unit outlines methods for identifying cyclic peptides that inhibit protein-protein interactions. Proteins of interest are cloned into a two-hybrid system engineered to operate in reverse, allowing the disruption of a protein complex to be coupled to cell growth. Cyclic peptide libraries are gen …
The histone lysine methyltransferase nuclear receptor-binding SET domain protein 2 (NSD2, also known as WHSC1/MMSET) is an epigenetic modifier and thought to play a driving role in oncogenesis. Both NSD2 overexpression and point mutations that increase its catalytic activity are associated with several human cancers. While NSD2 is an attractive therapeutic target, no potent, selective, and bioactive small molecule inhibitors of NSD2 have been reported to date, possibly due to the challenges of developing high-throughput assays for NSD2. Here, to establish a platform for the discovery and development of selective NSD2 inhibitors, we optimized and implemented multiple assays. We performed quantitative high-throughput screening with full-length wild-type NSD2 and a nucleosome substrate against a diverse collection of bioactive small molecules comprising 16,251 compounds. We further interrogated 174 inhibitory compounds identified in the primary screen with orthogonal and counter assays and with ...
The authors have retracted this article [1] because data shown in Figures 1-4 duplicate data in Figures 1, 2, 5, 6 and 8 in a previously published article by a different author group [2]. Yu Sun, Zhen Tian and Sui-Hui Li agree with this retraction. Xue-Feng Jiang and Shuang-Xi Zhu have not responded to correspondence from the editor or publisher about this retraction. The online version of this article contains the full text of the retracted article as electronic supplementary material. References [1] Xue-Feng Jiang, Zhen Tian, Shuang-Xi Zhu, Sui-Hui Li & Yu Sun. A novel small-molecule inhibitor suppresses colon cancer metastasis through inhibition of metastasis-associated in colon cancer-1 transcription. Invest New Drugs (2020). https://doi.org/10.1007/s10637-020-00957-8 [2] Manisha Juneja, Dennis Kobelt, Wolfgang Walther, Cynthia Voss, Janice Smith, Edgar Specker, Martin Neuenschwander, Björn-Oliver Gohlke, Mathias Dahlmann, Silke Radetzki, Robert Preissner, Jens Peter von Kries, Peter ...
Novartis Institutes for BioMedical Research, Cambridge, USA. Affinity proteomics and target identification for small molecule drug candidates. Affinity proteomics has become a valuable tool in preclinical small molecule drug discovery, in particular in the context of target identification and elucidation of the mechanism of action for drug candidates from phenotypic and pathway-centric approaches to drug discovery. Quantitative chemoproteomics, employing variations of a competition-based approach to small molecule affinity chromatography and mass spectrometry-based protein identification and quantitation, identifies cellular protein interactors and thus potential targets of drug candidates under conditions approximating the disease-relevant in vivo situation. Several examples will be presented and discussed in the context of orthogonal approaches to the generation of target hypotheses. On the other hand, the identification of protein-protein interactions using e.g. an affinity-tagged bait ...
At the end of the course, the student will know how organic chemistry, and in particular drug-like chemical diversity (assembled collections of different small organic molecules), can help in the identification and the characterization of new molecular targets; and will have acquired the necessary rudiments to understand the process of rational / computational design of small molecule modulators of either structurally characterized molecular targets (structure-based drug design, SBDD; fragment-based drug design, FBDD), or of non-structurally characterized molecular targets through their known ligands (ligand-based drug design, LBDD). Moreover, the student will acquire, besides the basic knowledge of NMR spectroscopy, also skills on different interaction techniques and learn how nuclear magnetic resonance can be important for the study of ligand-receptor interactions and for the development of new biologically active molecules ...
Current Research and Scholarly Interests We are interested in the structure, dynamics and function of eukaryotic transport proteins mediating ions and major nutrients crossing the membrane, the kinetics and regulation of transport processes, the catalytic mechanism of membrane embedded enzymes and the development of small molecule modulators based on the structure and function of membrane proteins. ...
0009]These same Rho kinase inhibitors are cell permeable, and cause changes in cytoskeletal function and cell behavior consistent with loss of Rho kinase activity, similar to effects of the trans-dominant inhibitory mutants. Effects have been observed both in cultured cells in vitro and in physiologically responsive tissues in vivo [Nagumo, H. et al., 2000, Am J Physiol Cell Physiol. 278:C57-C65; Sinnett-Smith, J. et al., 2001, Exp Cell Res. 266:292-302; Chrissobolis, S. and Sobey, C. G., 2001, Circ Res. 88:774-779; Honjo, M. et al., 2001, Invest Ophthalmol Vis Sci. 42:137-144; Takahara, A. et al., 2003, Eur J Pharmacol. 460:51-57; Fournier, A. E. et al., 2003, J Neurosci. 23:1416-1423; Rikitake, Y. et al., 2005, Stroke. 36:2251-2257; Slotta, J. E. et al. 2006, Inflamm Res. 55:364-367; Ying, H. et al., 2006, Mol Cancer Ther. 5:2158-2164]. The correlation between small molecule inhibition of Rho kinases and changes in cell behavior both in vitro and in vivo (e.g., vascular smooth muscle ...
Discussions of therapeutic suppression of hedgehog (Hh) signaling almost exclusively focus on receptor antagonism; however, hedgehogs biosynthesis represents a unique and potentially targetable aspect of this oncogenic signaling pathway. Here, we review a key biosynthetic step called cholesterolysis from the perspectives of structure/function and small molecule inhibition. Cholesterolysis, also called cholesteroylation, generates cholesterol-modified Hh ligand via autoprocessing of a hedgehog precursor protein. Post-translational modification by cholesterol appears to be restricted to proteins in the hedgehog family. The transformation is essential for Hh biological activity and upstream of signaling events. Despite its decisive role in generating ligand, cholesterolysis remains conspicuously unexplored as a therapeutic target.
TY - JOUR. T1 - Glioblastoma cell growth is suppressed by disruption of fibroblast growth factor pathway signaling. AU - Loilome, Watcharin. AU - Joshi, Avadhut D.. AU - ap Rhys, Colette M.J.. AU - Piccirillo, Sara. AU - Vescovi, Angelo. AU - Gallia, Gary L.. AU - Riggins, Gregory J.. PY - 2009/4/8. Y1 - 2009/4/8. N2 - The Fibroblast Growth Factor (FGF) signaling pathway is reported to stimulate glioblastoma (GBM) growth. In this work we evaluated the effect of FGF2, FGF receptor (FGFR), and small molecule inhibition on GBM cells grown in traditional media, or cultured directly in stem-cell media. These lines each expressed the FGFR1, FGFR3 and FGFR4 receptors. Addition of FGF2 ligand showed significant growth stimulation in 8 of 10 cell lines. Disruption of FGF signaling by a neutralizing FGF2 monoclonal antibody and FGFR1 suppression by RNA interference both partially inhibited cell proliferation. Growth inhibition was temporally correlated with a reduction in MAPK signaling. A receptor ...
Flavia Amadeu de Oliveira, Ph.D.. I am pleased and delighted for being the recipient of ASBMR Fund for Research and Education Research Grant 2019. I am currently investigating the molecular targets driving osteosarcoma metastasis, focusing specifically on FGFR and mTOR signalling. My work has so far demonstrated that small molecule inhibition of these pathways could serve as a potential therapy for inhibiting metastasis in osteosarcoma patients. The transcriptional and biochemical mechanisms underlying this effect are not known and therefore this award will help me to take a global approach through analysing and bridging together large genomic and proteomic data sets. Well-established training courses will provide me with additional expertise which I will be using for current and future research projects with a liberty to analyse data based on my independent biological questions. This award will be used in part to obtain bulk RNA-seq and proteomic data of tumour cells excised from different ...
Poly-α2,8-sialic acid (PSA) has been implicated in numerous normal and pathological processes, including development, neuronal plasticity, and tumor metastasis. We report that cell surface PSA expression can be reversibly inhibited by a small molecule,N-butanoylmannosamine (ManBut). Inhibition occurs through a metabolic mechanism in which ManBut is converted to unnatural sialic acid derivatives that effectively act as chain terminators during cellular PSA biosynthesis. N-Propanoylmannosamine (ManProp), which differs from ManBut by a single methylene group, did not inhibit PSA biosynthesis. Modulation of PSA expression by chemical means has a role complementary to genetic and biochemical approaches in the study of complex PSA-mediated events. ...
BACKGROUND: 15-Hydroxyprostaglandin dehydrogenase (15-PGDH, EC 1.1.1.141) is the key enzyme for the inactivation of prostaglandins, regulating processes such as inflammation or proliferation. The anabolic pathways of prostaglandins, especially with respect to regulation of the cyclooxygenase (COX) enzymes have been studied in detail; however, little is known about downstream events including functional interaction of prostaglandin-processing and -metabolizing enzymes. High-affinity probes for 15-PGDH will, therefore, represent important tools for further studies. PRINCIPAL FINDINGS: To identify novel high-affinity inhibitors of 15-PGDH we performed a quantitative high-throughput screen (qHTS) by testing |160 thousand compounds in a concentration-response format and identified compounds that act as noncompetitive inhibitors as well as a competitive inhibitor, with nanomolar affinity. Both types of inhibitors caused strong thermal stabilization of the enzyme, with cofactor dependencies correlating with
Video articles in JoVE about embryo mammalian include Isolation and Culture of Embryonic Mouse Neural Stem Cells, Isolation of Embryonic Ventricular Endothelial Cells, Genetic Manipulation of the Mouse Developing Hypothalamus through In utero Electroporation, Separation of Mouse Embryonic Facial Ectoderm and Mesenchyme.
1. Lineage specific transcription factors.. We are using genetic and biochemical approaches to define the molecular mechanisms through which lineage-specific transcriptional regulators orchestrate self-renewal and differentiation, focussing on SOX, FOX and bHLH families. These lie at the heart of cell fate decision-making by neural stem and progenitor cells during development and within brain tumours.. 2. Chemical and genetic screening. We are carrying out image-based small molecule screens to search for new agents and pathways that can modulate self-renewal and differentiation of normal and glioblastoma-derived neural stem cells. 3. Epigenetic programming and reprogramming. We are investigating whether changes to the epigenome within glioblastoma-derived cancer stem cells enable suppression of malignant properties. We are using both direct differentiation as well as nuclear reprogramming strategies to test this.. 4. Genome editing. Designer transcription factors and nucleases (TALENs or ...
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0031]The procedure for molecular docking involves: 1) selection of structural pockets in PKCiota suitable for interactions with drug-like small compounds, and 2) molecular docking simulations where each one of approximately 300,000 small compounds (MW,500) is positioned in the selected structural pocket and scored based on predicted polar (e.g., H bond) and non-polar (e.g. Van der Waals) interactions. The top 30 scoring compounds for each selected structural pocket were obtained for use in functional assays. Docking calculations were performed with the Oct. 15, 2002 development version of DOCKv5.1.0. molecular docking calculations The coordinates for the crystal structure PKC, PDB code 1ZRZ, was used. The molecular surface of the structure was explored using sets of spheres to describe potential binding pockets. The spheres literally fill in the available pocket spaces where a ligand might be able to form a complex. DOCK uses the spheres as a guide to search for orientations of each compound ...
With more than 10 years of accumulation, KBP has built a small molecule compound library with over 3,000,000 chemical compounds consisting of compounds designed and synthesized by KBP with unique chemical structures and high potency, compounds synthesized based on different core structures that cover almost all known core structures, and a natural product library of compounds extracted from plants, marine organisms and microorganisms.. Coupled with our bio-evaluation technology platform, the compound library enables KBP to identify and progress unique drugs that fit global unmet medical need quickly and efficiently.. Over 100 lead compounds have been screened from the library, and 3 compounds have entered into international clinical development.. ...
Marine soft corals are known to produce a wide array of secondary metabolites, particularly diterpenoids and steroids, and often characterized by uncommon structural features and potent bioactivities. The remarkable abundance and diversity of bioactive small molecule which have been isolated from soft corals have made these organisms an important source of new drug candidates for human diseases, particularly for their anti-inflammatory activity. In this paper, the authors reported anti-inflammatory marine natural products isolated from diverse species of soft corals determined in vitro by their inhibition of lipopolysaccharide-induced expression of inducible NO synthase and cyclooxygenase-2 in murine macrophage cells (RAW 264.7 ...
CGRP receptor small molecule antagonists. Several small molecule antagonists have been shown to block the binding of CGRP to its receptors. They are chemically un-related but they all do the same job and collectively referred as gepants. All gepants that have been tested to date are effective in patients with migraine (3-5). Olcegepant was the first to be discovered but since then others have been successfully tested - telcagepant, ubrogepant, MK-3207, BI 44370 TA and BMS-927711. However, further development of gepants has been clouded by the discovery of liver toxicity with long term use of the earlier gepants. Ubrogepant and atogepant are newly developed gepants that are chemically different from telcagepant and the other gepants. Ubrogepant has completed phase IIb testing and is being evaluated in phase III trials for acute relief of migraine. To date, results indicate that ubrogepant has good efficacy, comparable to that of triptans, with no incidence of elevated liver enzymes or other ...
Bacterial infections are increasingly difficult to treat owing to the spread of antibiotic resistance. A major concern is Gram-negative bacteria, for which the discovery of new antimicrobial drugs has been particularly scarce. In an effort to accelerate early steps in drug discovery, the EU-funded AEROPATH project aims to identify novel targets in the opportunistic pathogen Pseudomonas aeruginosa by applying a multidisciplinary approach encompassing target validation, structural characterization, assay development and hit identification from small-molecule libraries. Here, the strategies used for target selection are described and progress in protein production and structure analysis is reported. Of the 102 selected targets, 84 could be produced in soluble form and the de novo structures of 39 proteins have been determined. The crystal structures of eight of these targets, ranging from hypothetical unknown proteins to metabolic enzymes from different functional classes (PA1645, PA1648, PA2169, ...
Rheumatoid arthritis patients who do not respond to treatment with biologic therapies may find relief in baricitinib, a new small molecule drug, according to the results of a phase III study published in The New England Journal of Medicine online, 31 March 2016 ...
Chemical library technologies have brought about dramatic changes in the drug discovery process, and, though still evolving, they have become an integral part of ongoing drug discovery research. In Ch
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Observed deficits in protein phosphatase 2A (PP2A) function in a variety of human cancers have stimulated drug discovery efforts aimed at restoring PP2A function to inhibit tumor growth. Work published by Sangodkar et al. in this issue of the JCI describes the characterization of orally available small molecule activators of PP2A (SMAPs). These SMAPs attenuated mitogenic signaling and triggered apoptosis in KRAS-mutant lung cancer cells and inhibited tumor growth in murine models. Tumors with mutations in the SMAP-binding site of the PP2A A subunit displayed resistance to SMAPs. Future studies that identify the PP2A-regulated events targeted by SMAPs should guide critical decisions about which cancers might be best treated with these molecules. This study provides encouraging evidence in favor of SMAPs as potential anticancer drugs ...
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The Wnt/ß-catenin signaling pathway controls important cellular events during development and often contributes to disease when dysregulated. Using high throughput screening we have identified a new small molecule inhibitor of Wnt/ß-catenin signaling, WIKI4. WIKI4 inhibits expression of ß-catenin target genes and cellular responses to Wnt/ß-catenin signaling in cancer cell lines as well as in human embryonic stem cells. Furthermore, we demonstrate that WIKI4 mediates its effects on Wnt/ß-catenin signaling by inhibiting the enzymatic activity of TNKS2, a regulator of AXIN ubiquitylation and degradation. While TNKS has previously been shown to be the target of small molecule inhibitors of Wnt/ß-catenin signaling, WIKI4 is structurally distinct from previously identified TNKS inhibitors.
The advent of Gleevec® (imatinib) less than 10 years ago was a landmark for utilizing small molecule compounds as kinase inhibitor drugs (1-3). This type of drug is usually directed against one specific kinase whose malfunctioning plays a key role in the given disease. Generally these drugs are thought to be selective, easy to modify, and effective. As the molecular principles of various diseases are better understood, kinase inhibitors are being developed in various fields with cancer remaining the predominant one (4). Kinase inhibitor compounds constitute about 30% of all drug development programs in the pharmaceutical industry (5).. Kinase inhibitor drugs are typically developed with a targeted and rational strategy, often focusing on a kinase known to be involved in the etiology of a disease. Large libraries of chemical compounds, for example ATP analogs, are screened in vitro against the activity of this kinase, and their effects on a panel of manually selected kinases with similar ...
Plans to almost double access to free early learning and childcare in one early years centre in Prestwick have been agreed by South Ayrshire Council. The pilot project forms part of a modernisation pa
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Mr Smith said: The picture for Glasgow Prestwick Airport is a positive one - we believe our passenger numbers have bottomed out and are on the up again, cargo income is consistent in spite of changes in the wider market, military income is growing, property occupancy are at an all-time high and early indications for the last financial year show that our losses are less than predicted.. The turnaround will be challenging and will take time, but it has started and this plan will build upon this.. The Scottish Government has always stated that they would like to return the business to the private sector and this is a fundamental pillar of our plan.. We are working to make the business an attractive prospect for a private investor to come in and build upon this strategy - someone that can bring in additional funds to upgrade our infrastructure and facilities and attract even more business.. If we are able to do this, we could speed up our turnaround.. Airport chairman Andrew Miller said the ...
...BOSTON Mass. (Feb. 24 2008)Why do nearly 1 million people taking cho...A new chemical toolkit provides the first clinical explanation for the...A research team led by Harvard Medical School assistant professor and ...Over the last few decades mitochondria have increasingly been underst...,New,chemical,tool,kit,manipulates,mitochondria,,reveals,insights,into,drug,toxicity,biological,biology news articles,biology news today,latest biology news,current biology news,biology newsletters
Principal Research Interests: medicinal chemistry and drug discovery, targeted anti-cancer agents.. The medicinal chemistry team (C Cano, BT Golding, IR Hardcastle, and M Waring) is part of the Drug Discovery Group within the NICR. Working closely with basic cancer biologists, structural biologists, pharmacologists, imaging specialists, and clinical scientists, the overall aim of the programme is to discover novel small-molecule inhibitors of cancer targets which can be developed into new treatments for cancer patients. Targets are selected based on an understanding of the underlying cancer biology and their clinical relevance. Current projects include the discovery of small-molecule MDM2-p53 protein protein interactions, the discovery of small-molecule ERK5 inhibitors, and hit-discovery studies for other novel cancer targets.. Contemporary, medicinal chemistry methods are used in all projects. including high throughput screening to identify hit compounds (through external collaborations), and ...
Milne JC, Lambert PD, Schenk S, Carney DP, Smith JJ, Gagne DJ, Jin L, Boss O, Perni RB, Vu CB, Bemis JE, Xie R, Disch JS, Ng PY, Nunes JJ, Lynch AV, Yang H, Galonek H, Israelian K, Choy W, Iffland A, Lavu S, Medvedik O, Sinclair DA, Olefsky JM, Jirousek MR, Elliott PJ, Westphal CH. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature. 2007;450:712-16 ...
It is an interdisciplinary section devoted to all aspects of chemical biology, a rapidly growing field at the interface of chemistry and biology as well as related biomedical fields. The section offers a peer-reviewed and open access publication option to chemists, biologists and other researchers that develop and apply chemical tools to investigate biological systems and processes. Chemical Biology covers advances in a wide range of topics in the field, from new molecular tools and techniques, to their applications to address biological questions at the molecular or cellular level. The focus is on molecules and methods used to identify, visualize, probe or validate the biological functions of small molecules or biomolecules and their biological pathways. Examples include: the design, synthesis, and use of novel molecular systems as tools to study biology; the use of special chemical techniques, such as click chemistry and molecular imaging, to study the actions of small and large biomolecules ...
Buy and find information on Product Number c08885, 5-amino-2,4,6-triiodoisophthalic acid, CAS Number 35453-19-1, 8,8g, We sell fine chemicals, building blocks and small molecule compounds to the pharmaceutical, drug discovery, agrochemical and biotechnology companies, university or institute scientists.
This work proposes to use the marine algal toxin yessotoxin (YTX) to establish reference model experiments to explore medically valuable effects from induction of multiple cell death pathways. YTX is one of few toxins reported to make such induction. It is a small molecule compound which at low concentrations can induce apoptosis in primary cultures, many types of cells and cell lines. It can also induce a non-apoptotic form of programmed cell death in BC3H1 myoblast cell lines. The present contribution reviews arguments that this type of induction may have principal interest outside this particular example. One principal effect of medical interest may be that cancer cells will not so easily adapt to the synergistic effects from induction of more than one death pathway as compared to induction of only apoptosis.
Giving solutions to the problems of crystallization and crystallography. Protein and small molecule compounds crystallization, Structural Crystallography, Space logistic support for crystallization experiments, tailor-made crystals of high purity.
Giving solutions to the problems of crystallization and crystallography. Protein and small molecule compounds crystallization, Structural Crystallography, Space logistic support for crystallization experiments, tailor-made crystals of high purity.