Abstract 509: DM5167, a novel selective PARP1 inhibitor, efficiently reduces growth of triple-negative breast cancers

Abstract

Poly (ADP-ribose) polymerase 1 (PARP1) has been portrayed as a synthetic lethal target in cancers with homologous recombination deficiency. As all four PARP inhibitors on the market target both PARP1 and PARP2 isotypes, hematological toxicity issue emerged by PARP2 inhibition. To address the unmet need, we screened and optimized compounds exempt from the toxicity issue. Here, we present DM5167 as a new molecular entity with 0.41 nM of IC50 on the catalytic activity of PARP1. In addition, DM5167 exhibits an inhibitory profile against various PARP isotypes that differs from the four commercial PARP inhibitors. Specifically, DM5167 shows selectivity for PARP1 6.88 and 347.83 fold greater than PARP2 in the in vitro enzyme assay and DNA trapping assay, respectively. This contrasts with the corresponding PARP1/PARP2 selectivity values of 0.14 and 0.89 fold for olaparib, respectively. Moreover, DM5167 showed higher selectivity than AZD5305 in the enzymatic assay. The GLP toxicity studies assigned DM5167 as a safe compound based on its high NoAEL value, a general toxicity parameter. In addition, the safety margin of DM5167 was acceptable, indicating that DM5167 is a plausible drug candidate. To find suitable indications, we screened various human cancer cell lines using their inhibitory potentials against proliferation and colony formation. Several hits were seen in triple-negative breast cancer cell lines including MDA-MB-231, MDA-MB-436, MDA-MB-468 and HCC1395. In an orthotopic xenograft experiment in which MDA-MB-231 cells were implanted, oral administration of 50mpk of DM5167 inhibited tumor growth by 45.8%. In contrast, olaparib failed to reduce xenograft tumors derived from MDA-MB-231 cells. Collectively, these studies present DM5167 as an attractive anti-TNBC drug candidate. Citation Format: Sujin Nam, Jiyoung Chae, Kyung-Ok Cho, Tae-Sung Koo, Jungho Kim, Myungeun Jung, Jeongmin Kim, Eunhee Kim. DM5167, a novel selective PARP1 inhibitor, efficiently reduces growth of triple-negative breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 509.