MS275 is a benzamide histone deacetylase inhibitor

PARP inhibitors have been evaluated in clinical trials either MS-275 as single agents, with an emphasis on patients Ridaforolimus carrying BRCA mutations, or in combination with DNA damaging therapies . Olaparib has demonstrated single agent activity in breast or ovarian cancer patients with germline mutations in BRCA1/2 ; an over 40% response rate has been reported in patients with BRCA mutant ovarian cancer, especially in patients with platinum sensitive disease . The Cancer Genome Atlas Research Project recently reported on the molecular aberrations in high grade serous ovarian adenocarcinoma, demonstrating a defect in the HR pathway in half of the 489 tumors analyzed . These results suggest that ovarian cancer patients with sporadic abnormalities in the HR pathway impairing DNA repair might benefit from treatment with PARP inhibitors. Similar abnormalities in DNA repair pathways have been reported in primary peritoneal cancers, and in patients with TNBC, forming the basis for recent clinical trials that have explored the use of PARP inhibitors in such patient populations . AGI-5198 Tumor types with defects in other DNA repair pathways, such as tumors with microsatellite instability, may also be susceptible to inhibition of the BER pathway . Despite the evaluation of PARP inhibition in a number of clinical trials, the degree and duration of inhibition required for optimal clinical benefit has yet to be established . This has resulted in the continuation of studies that have explored higher PARP inhibitor doses, well beyond those demonstrated to result in near-complete inhibition of PARP activity in clinical tumor samples; the results of some of these trials, such as the ICEBERG study, have suggested a dose response for deriving clinical benefit from PARP inhibitors . A major focus for the future clinical development of PARP inhibitors is to determine whether or not potentiating chemotherapy- or radiation-induced DNA damage in patients without known defects in DDR is either possible PNU-120596 or fruitful. Enhancement of DNA damage by the addition of a PARP inhibitor to a topoisomerase I poison has been demonstrated in tumor biopsies and circulating tumor cells by measurement of gH2AX foci, a marker of DNA double strand breaks, in patients treated with veliparib and topotecan compared to those receiving topotecan alone . However, the development of PARP inhibitors as chemopotentiating agents Staurosporine has been limited by an increase in observed toxicities, mainly myelosuppression, necessitating dose reductions of the cytotoxic chemotherapeutic agent and the PARP inhibitor . This raises the question of whether administering the combination is more efficacious than administering full doses of the chemotherapeutic agent alone, as well as the need to design clinical trial strategies to improve the therapeutic index of these combinations. It seems likely that to optimize the use of PARP inhibitors in the future will require the development of predictive assays to determine the presence of unsuspected defects in DDR pathways in tumors. It also presents an opportunity to rationally develop combinations of PARP inhibitors with new classes of DNA repair inhibitors that are on the horizon, and classical cytotoxic agents .

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