Abstract LB_C11: Small-molecule bifunctional inhibitors of PARP1/2 and HDAC enzymes

Abstract

Abstract Background: Poly(ADP-ribose) polymerase (PARP) plays a major role in DNA repair and PARP inhibitors (PARPi) have shown promise for the treatment of cancers with DNA damage repair defects, such as BRCA mutations. PARPi are currently approved for treatment of BRCA-mutated cancers and as a maintenance therapy for patients who have responded to platinum-based chemotherapy. To improve efficacy, overcome resistance, and expand the usage of PARPi to non-BRCA mutated disease, combination therapies with PARPi have emerged as an area of interest. Histone deacetylases (HDACs) play a major role in DNA repair and inhibition of HDACs has been shown to reduce tumor growth. PARPi combined with HDACi has shown enhanced efficacy in pre-clinical studies in various cancers, and a clinical trial of olaparib and vorinostat against metastatic breast cancer is ongoing. However, combination therapies can be limited clinically due to overlapping toxicities and differing pharmacokinetics. Here, we report the efficacy of a novel class of bifunctional small-molecule compounds (kt-3000) with both PARP1 and PARP2 inhibitory and HDAC inhibitory activities. Methods: PARP1 and PARP2 activity was measured using Trevigen Universal Colorimetric PARP Assay kit and BPS Bioscience PARP2 Colorimetric Assay kit respectively. HDAC activity was measured using HeLa nuclear extracts and a fluorogenic peptide-based biochemical assay. In vitro metabolism was determined by HPLC after incubation with human liver microsomes for up to 45 mins. Pharmacokinetic profiling was examined in mice up to 6 h after oral/intraperitoneal (IP) dosing. Results: kt-3000 compounds showed potent inhibition of PARP1 and PARP2 activity with IC50 values comparable to olaparib (low nM) and inhibition of HDACs with IC50 values in the low µM range. Metabolic and pharmacokinetic profiling suggest drug-like qualities in the class. Conclusion: kt-3000 molecules demonstrate potent inhibition of PARP1/2 and HDAC activities, with suitable pharmacokinetic properties for oral delivery. Further refinement and development of these bifunctional single-molecule inhibitors may offer a novel therapeutic opportunity for treatment of cancers with and without DNA damage repair defects. Citation Format: Sarah Truong, Louise Ramos, Beibei Zhai, Jay Joshi, Fariba Ghaidi, Mona Marzban, Hans Adomat, Charles Chen, John Langlands, Dennis Brown, Jeffrey Bacha, Colin Collins, Poul Sorensen, Wang Shen, Mads Daugaard. Small-molecule bifunctional inhibitors of PARP1/2 and HDAC enzymes [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_C11.