The research in this thesis is focused on the design, synthesis, and biological evaluation of indenoisoquinolines that inhibit the human topoisomerase IB enzyme (Top1). (purdue.edu)
Although the present arsenal of Top1 inhibitors is effective in the treatment of solid tumors, their common camptothecin-based structure is plagued by physicochemical and pharmacological issues. (purdue.edu)
In the second effort, thirty-two new indenoisoquinolines substituted with linear and cyclic carbohydrate-derived or carbohydrate-mimetic moieties were designed and synthesized as potential Top1 inhibitors. (purdue.edu)
The rationale for this substitution and the design process were aided by the X-ray crystal structures of an indenoisoquinoline and an indolocarbazole glycoside bound separately to the Top1-DNA cleavage complex. (purdue.edu)
The third effort was focused on making improvements to a promising class of indenoisoquinoline Top1 inhibitors, albeit one with a potentially serious toxicology risk. (purdue.edu)
He discovered the indenoisoquinolines as novel Top1 inhibitors, which are in clinical development, and the mitochondrial topoisomerase gene, TOP1mt. (cancer.gov)
Three of his indenoisoquinoline TOP1 inhibitors are in Phase 1/2 clinical development (Thomas & Pommier, Clin Cancer Res 2019): LMP400 (Indotecan), LMP776 (Indimitecan) and LMP744. (cancer.gov)
2020). Based on their promising clinical activity and their superior medicinal properties over the camptothecins, the indenoisoquinolines represent the first non-camptothecin TOP1 inhibitors for the treatment of cancers. (cancer.gov)
Recently, Dr. Pommier demonstrated that misincorporated ribonucleotides (the most frequent DNA alteration) trap topoisomerases, which convert them to toxic and mutagenic nicks by TOP1 (Kim et al. (cancer.gov)
2018). While studying the tyrosyl-DNA-phosphodiesterase (TDP1 and TDP2) repair pathways for the excision of topoisomerases from DNA, Dr. Pommier revealed that TDP1 repairs a broad range of 3'-blocking lesions in addition to TOP1 (Murai et al. (cancer.gov)
Inhibition3
OBJECTIVE: To study aimed to identify crucial molecular features and structural requirements for potent topoisomerase-I inhibition. (bvsalud.org)
RESULTS: The optimized QSAR model revealed the importance of specific descriptors, including molecular volume, Verloop B2, and Weiner topological index, providing essential insights into effective topoisomerase-I inhibition. (bvsalud.org)
He revealed the interfacial inhibition paradigm based on molecular mechanisms of topoisomerase inhibitors, and has championed its broad relevance for molecular pharmacology and drug discovery. (cancer.gov)
Derivatives2
METHODS: A comprehensive two-dimensional (2D) QSAR analysis was performed on a series of 49 indenoisoquinoline derivatives using TSAR3.3 software. (bvsalud.org)
Title : "Sar of indenoisoquinoline derivatives as topoisomerase inhibitior" - A review. (kvmpharmacycollege.in)
Antony1
Dr. Pommier reported the first TDP1 inhibitors (Antony et al. (cancer.gov)
Chem1
J Med Chem 2005) and extended it to macromolecular complexes involving proteins and protein-RNA complexes beyond topoisomerases (Pommier et al. (cancer.gov)
Molecular1
CONCLUSION: 2D QSAR analysis offers valuable molecular insights into indenoisoquinoline-based topoisomerase-I inhibitors, supporting their potential as anti-lung cancer agents. (bvsalud.org)
Topological2
DNA topoisomerases (or topoisomerases) are enzymes that catalyze changes in the topological state of DNA, interconverting relaxed and supercoiled forms, linked (catenated) and unlinked species, and knotted and unknotted DNA. (wikipedia.org)
The DNA topoisomerases prevent and correct these types of topological problems. (wikipedia.org)
Potential1
Three compounds discovered in the Cushman laboratory are under investigation in humans and canines as potential anticancer drugs. (purdue.edu)
World1
Nucleic Acids Res 2007) and he is a world leader for the discovery of TDP1 and TDP2 inhibitors (Marchand et al. (cancer.gov)
Drug1
BACKGROUND: Indenoisoquinoline-based compounds have shown promise as topoisomerase-I inhibitors, presenting an attractive avenue for rational anticancer drug design. (bvsalud.org)
Studies1
He demonstrated the interfacial inhibitor mechanism by co-crystal studies (Ionaviciu et al. (cancer.gov)
Damage2
In parallel, Dr. Pommier has profoundly contributed to the elucidation of the repair pathways for topoisomerase-=induced DNA damage (Pommier et al. (cancer.gov)
He was the first to show that topoisomerases are trapped by DNA damage (by oxidative base lesions, base alkylation, DNA nicks) (Pourquier et al. (cancer.gov)
TOP116
10. The Indenoisoquinoline LMP517: A Novel Antitumor Agent Targeting both TOP1 and TOP2. (nih.gov)
These investigators are using small interfering RNAs (siRNAs), which selectively and systematically inhibit the activity of genes, to look for genes in breast cancer cells that can be targeted in combination with an existing class of cancer drugs, called Topoisomerase 1 poisons (TOP1). (nih.gov)
The investigators are conducting large-scale RNAi screens for novel targets that synergize with TOP1 inhibitors. (nih.gov)
The Pommier laboratory at the National Cancer Institute recently discovered a novel class of non-camptothecin TOP1 inhibitors, the indenoisoquinolines. (nih.gov)
The indenoisoquinolines have overcome limitations of the camptothecins in preclinical models and are among the most advanced anticancer drugs in the non-camptothecin TOP1 inhibitor class. (nih.gov)
The aim of this project is to use a large-scale siRNA screen to uncover novel pathways that determine the efficacy of TOP1 inhibitors. (nih.gov)
The investigators are using the triple-negative breast cancer cell line MDA-MB231 cells (previously validated as very effective for siRNA screen) and the clinically-relevant indenoisoquinoline TOP1 inhibitor NSC 725776 (LMP-776) and NSC 724998 (LMP-400) for the high-throughput screen at the NCATS Chemical Genomics Center. (nih.gov)
Hit validation is being performed using experiments in additional cell lines, and specificity is being determined by evaluating active genes in the context of non-TOP1 inhibitors (e.g., taxol and etoposide). (nih.gov)
These efforts will help discover new genomic biomarkers to predict the activity of TOP1 inhibitors and personalize therapies in cancer patients. (nih.gov)
Identification of new pathways may also lead to the development of novel therapies using small molecules or biologicals for the treatment of cancers in combination with TOP1 inhibitors. (nih.gov)
Ongoing studies are being performed with validated targets in additional cell lines and in the context of non-TOP1 inhibitors (e.g., taxol and etoposide). (nih.gov)
While expressing weak cytotoxicity on its own, ZW-1288 potentiates the clinical TOP2 inhibitors etoposide (ETP) and mitoxantrone in human prostate DU145 and CCRF-CEM leukemia and chicken lymphoma DT40 cells while not impacting the activity of the topoisomerase I (TOP1) inhibitor camptothecin or the PARP inhibitor olaparib. (omicsdi.org)
Three of his indenoisoquinoline TOP1 inhibitors are in Phase 1/2 clinical development (Thomas & Pommier, Clin Cancer Res 2019): LMP400 (Indotecan), LMP776 (Indimitecan) and LMP744. (nih.gov)
2020). Based on their promising clinical activity and their superior medicinal properties over the camptothecins, the indenoisoquinolines represent the first non-camptothecin TOP1 inhibitors for the treatment of cancers. (nih.gov)
Recently, Dr. Pommier demonstrated that misincorporated ribonucleotides (the most frequent DNA alteration) trap topoisomerases, which convert them to toxic and mutagenic nicks by TOP1 (Kim et al. (nih.gov)
2018). While studying the tyrosyl-DNA-phosphodiesterase (TDP1 and TDP2) repair pathways for the excision of topoisomerases from DNA, Dr. Pommier revealed that TDP1 repairs a broad range of 3'-blocking lesions in addition to TOP1 (Murai et al. (nih.gov)
Poisons3
2. Synthesis of cytotoxic indenoisoquinoline topoisomerase I poisons. (nih.gov)
Moreover, the most active compounds were investigated for being topoisomerase poisons or catalytic inhibitors using DNA nicking assay. (bvsalud.org)
Topoisomerase II (TOP2) poisons as anticancer drugs work by trapping TOP2 cleavage complexes (TOP2cc) to generate DNA damage. (omicsdi.org)
Type II topoisomerases3
They do this by binding to DNA and cutting the sugar-phosphate backbone of either one (type I topoisomerases) or both (type II topoisomerases) of the DNA strands. (wikipedia.org)
Type II topoisomerases were subsequently identified from bacterial viruses and eukaryotes. (wikipedia.org)
Eukaryotic type II topoisomerases (Top2? (omicsdi.org)
Indenoisoquinolines4
6. Novel indenoisoquinolines NSC 725776 and NSC 724998 produce persistent topoisomerase I cleavage complexes and overcome multidrug resistance. (nih.gov)
13. A systematic study of nitrated indenoisoquinolines reveals a potent topoisomerase I inhibitor. (nih.gov)
15. Nitrated indenoisoquinolines as topoisomerase I inhibitors: a systematic study and optimization. (nih.gov)
5. Differential induction of topoisomerase I-DNA cleavage complexes by the indenoisoquinoline MJ-III-65 (NSC 706744) and camptothecin: base sequence analysis and activity against camptothecin-resistant topoisomerases I. (nih.gov)
Tyrosyl-DNA phosphodiesterase 2 (TDP2) is a DNA repair enzyme that removes 5'-phosphotyrosyl blockages resulting from topoisomerase II (TOP2)-DNA cleavage complexes trapped by TOP2 inhibitors. (omicsdi.org)
Anticancer drugs (etoposide, doxorubicin, and mitoxantrone) and also Top2 oxidation and DNA helical alterations cause potentially irreversible Top2·DNA cleavage complexes (Top2cc), leading to Top2-linked DNA breaks. (omicsdi.org)
PARP1
Dr. Pommier made the landmark discovery that poly(ADPribose) polymerase (PARP) inhibitors act as anticancer agents by trapping PARP-DNA complexes (Murai et al. (nih.gov)
18. Design, synthesis, and biological evaluation of cytotoxic 11-alkenylindenoisoquinoline topoisomerase I inhibitors and indenoisoquinoline-camptothecin hybrids. (nih.gov)
Additionally, in silico molecular modeling study for eight most active cytotoxic compounds in five dose screening demonstrated interaction with DNA as well as distinctive binding pattern similar to the reference indenoisoquinoline, indicating that the newly discovered targets are supposed to be promising candidates as Topo I inhibitors. (bvsalud.org)
Complexes3
Proteolytic degradation of topoisomerase II (Top2) enables the processing of Top2·DNA and Top2·RNA covalent complexes by tyrosyl-DNA-phosphodiesterase 2 (TDP2). (omicsdi.org)
Dr. Pommier conceptualized the "interfacial inhibitors" mechanism based on his finding that DNA topoisomerase inhibitors act by trapping topoisomerase-DNA complexes (Capranico et al. (nih.gov)
J Med Chem 2005) and extended it to macromolecular complexes involving proteins and protein-RNA complexes beyond topoisomerases (Pommier et al. (nih.gov)
Etoposide1
Novel Deazaflavin Analogues Potently Inhibited Tyrosyl DNA Phosphodiesterase 2 (TDP2) and Strongly Sensitized Cancer Cells toward Treatment with Topoisomerase II (TOP2) Poison Etoposide. (omicsdi.org)
TDP27
Currently known TDP2 inhibitors lack cellular potency and/or permeability. (omicsdi.org)
We report herein two novel subtypes of the deazaflavin TDP2 inhibitor core. (omicsdi.org)
There is, however, no TDP2 inhibitor in clinical development at present. (omicsdi.org)
Of the reported TDP2 inhibitors, the deazaflavins are the most promising chemical class centered around the lead compound SV-5-153. (omicsdi.org)
ZW-1288 increases the uptake of ETP to a lesser extent than SV-5-153 and remained active in TDP2 knockout cells indicating that the deazaflavin TDP2 inhibitors have additional cellular effects that will have to be taken into account for their further development as TDP2 inhibitors. (omicsdi.org)
Nucleic Acids Res 2007) and he is a world leader for the discovery of TDP1 and TDP2 inhibitors (Marchand et al. (nih.gov)
Pommier3
In parallel, Dr. Pommier has profoundly contributed to the elucidation of the repair pathways for topoisomerase-=induced DNA damage (Pommier et al. (nih.gov)
Dr. Pommier reported the first TDP1 inhibitors (Antony et al. (nih.gov)
Dr. Pommier discovered the 6th vertebrate topoisomerase gene, TOP1MT (Zhang et al. (nih.gov)
Enzymes2
DNA topoisomerases (or topoisomerases) are enzymes that catalyze changes in the topological state of DNA, interconverting relaxed and supercoiled forms, linked (catenated) and unlinked species, and knotted and unknotted DNA. (wikipedia.org)
it is now called Escherichia coli (E. coli) topoisomerase I (topo I) and is a representative of the type IA family of enzymes. (wikipedia.org)
Phase1
Analyzing cell cycle and induction of apoptosis for the most active compound 4d, revealed growth arrest at the S phase in MDA-MB-435 cells similarly to indenoisoquinoline reference drug. (bvsalud.org)
Activity3
1. Bisindenoisoquinoline bis-1,3-{(5,6-dihydro-5,11-diketo-11H-indeno[1,2-c]isoquinoline)-6-propylamino}propane bis(trifluoroacetate) (NSC 727357), a DNA intercalator and topoisomerase inhibitor with antitumor activity. (nih.gov)
12. Synthesis and anticancer activity of simplified indenoisoquinoline topoisomerase I inhibitors lacking substituents on the aromatic rings. (nih.gov)
DNA relaxation assay for the latter compounds showed that 4d, 5b, and 6f exhibited excellent inhibitory activity with IC50 range of 2.553-4.495 µM as compared to indenoisoquinoline reference drug (IC50 = 3.911 ± 0.21 µM). (bvsalud.org)
Show1
He was the first to show that topoisomerases are trapped by DNA damage (by oxidative base lesions, base alkylation, DNA nicks) (Pourquier et al. (nih.gov)