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New Insights Into DNA Helicases as Druggable Targets for Cancer Therapy.

ABSTRACT: Small molecules that deter the functions of DNA damage response machinery are postulated to be useful for enhancing the DNA damaging effects of chemotherapy or ionizing radiation treatments to combat cancer by impairing the proliferative capacity of rapidly dividing cells that accumulate replicative lesions. Chemically induced or genetic synthetic lethality is a promising area in personalized medicine, but it remains to be optimized. A new target in cancer therapy is DNA unwinding enzymes known as helicases. Helicases play critical roles in all aspects of nucleic acid metabolism. We and others have investigated small molecule targeted inhibition of helicase function by compound screens using biochemical and cell-based approaches. Small molecule-induced trapping of DNA helicases may represent a generalized mechanism exemplified by certain topoisomerase and PARP inhibitors that exert poisonous consequences, especially in rapidly dividing cancer cells. Taking the lead from the broader field of DNA repair inhibitors and new information gleaned from structural and biochemical studies of DNA helicases, we predict that an emerging strategy to identify useful helicase-interacting compounds will be structure-based molecular docking interfaced with a computational approach. Potency, specificity, drug resistance, and bioavailability of helicase inhibitor drugs and targeting such compounds to subcellular compartments where the respective helicases operate must be addressed. Beyond cancer therapy, continued and new developments in this area may lead to the discovery of helicase-interacting compounds that chemically rescue clinically relevant helicase missense mutant proteins or activate the catalytic function of wild-type DNA helicases, which may have novel therapeutic application.

SUBMITTER: Datta A

PROVIDER: S-EPMC6028597 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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New Insights Into DNA Helicases as Druggable Targets for Cancer Therapy.

Datta Arindam A Brosh Robert M RM

Frontiers in molecular biosciences 20180626

Small molecules that deter the functions of DNA damage response machinery are postulated to be useful for enhancing the DNA damaging effects of chemotherapy or ionizing radiation treatments to combat cancer by impairing the proliferative capacity of rapidly dividing cells that accumulate replicative lesions. Chemically induced or genetic synthetic lethality is a promising area in personalized medicine, but it remains to be optimized. A new target in cancer therapy is DNA unwinding enzymes known ...[more]

PMID: 29998112

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Project description:According to the National Comprehensive Cancer Network and the American Society of Clinical Oncology, the standard treatment for pancreatic cancer (PC) is gemcitabine and fluorouracil. Other chemotherapeutic agents have been widely combined. However, drug resistance remains a huge challenge, leading to the ineffectiveness of cancer therapy. Therefore, we are trying to discover new treatments for PC by utilizing genomic information to identify PC-associated genes as well as drug target genes for drug repurposing. Genomic information from a public database, the cBio Cancer Genomics Portal, was employed to retrieve the somatic mutation genes of PC. Five functional annotations were applied to prioritize the PC risk genes: Kyoto Encyclopedia of Genes and Genomes; biological process; knockout mouse; Gene List Automatically Derived For You; and Gene Expression Omnibus Dataset. DrugBank database was utilized to extract PC drug targets. To narrow down the most promising drugs for PC, CMap Touchstone analysis was applied. Finally, ClinicalTrials.gov and a literature review were used to screen the potential drugs under clinical and preclinical investigation. Here, we extracted 895 PC-associated genes according to the cBioPortal database and prioritized them by using five functional annotations; 318 genes were assigned as biological PC risk genes. Further, 216 genes were druggable according to the DrugBank database. CMap Touchstone analysis indicated 13 candidate drugs for PC. Among those 13 drugs, 8 drugs are in the clinical trials, 2 drugs were supported by the preclinical studies, and 3 drugs are with no evidence status for PC. Importantly, we found that midostaurin (targeted PRKA) and fulvestrant (targeted ESR1) are promising candidate drugs for PC treatment based on the genomic-driven drug repurposing pipelines. In short, integrated analysis using a genomic information database demonstrated the viability for drug repurposing. We proposed two drugs (midostaurin and fulvestrant) as promising drugs for PC.

Dataset Information

New Insights Into DNA Helicases as Druggable Targets for Cancer Therapy.

Publications

New Insights Into DNA Helicases as Druggable Targets for Cancer Therapy.

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