Abstract LB269: XZP-6924: A potent and highly selective USP1 inhibitor with the potential to improve efficacy and overcome resistance to PARP inhibitors

Abstract Genomic instability exists in most cancer cells, making them more dependent on certain DDR repair pathways. Existing research shows that inhibition of the DNA damage response (DDR) pathway stresses cell replication and survival. Drugs targeting the DDR pathway are effective in the treatment of many types of cancers, such as the approved Poly (ADP-ribose) polymerase (PARP) inhibitors that cause synthetic lethality to the cancers harboring BRCA1/2 mutations and other homologous repair deficiencies (HRD). Although PARP inhibitors have good clinical performance, not all patients respond to PARP inhibitor treatments. In addition, the effectiveness of PARP inhibitors in clinics is also limited by the rise of treatment-related drug resistance. Ubiquitin-specific protease 1 (USP1) is involved in DNA damage repair processes, including translesion synthesis and Fanconi anemia pathways. It has been well documented that USP1 deficiency leads to replication fork instability and synthetic lethality to HRD. Combination of USP1 inhibitors with PARP inhibitors synergistically targets BRCA1/2 mutant cancers, thereby enhancing the antitumor effect and reducing drug resistance to PARP inhibitors. We have developed a potent and highly selective USP1 inhibitor, XZP-6924. The selective inhibition of USP1 by XZP-6924 results in the accumulation of mono-ubiquitinated USP1 substrates, for example, proliferating nuclear antigen (PCNA), leading to DNA double-strand breaks (DSBs) and widespread DNA damage accumulation that contributes to cell death. In vitro data reveal that XZP-6924, when combined with Olaparib (PARPi), displays significantly enhanced activities in multiple Olaparib-resistant HRD tumor cells. In CDX and PDX mouse tumor models, XZP-6924 at low doses demonstrates synergy and superior efficacy with sustained tumor regression when combined with a PARP inhibitor (Olaparib). Furthermore, XZP-6924 possesses favorable ADME properties and pharmacokinetic profiles in preclinical animal species. Preliminary toxicology study data indicate that XZP-6924 is well tolerated with a favorable safety margin. In conclusion, XZP-6924 is a potent and highly selective USP1 inhibitor that has the potential for the combination therapy with PARP inhibitors to increase efficacy and overcome some primary and acquired resistance to PARP inhibitors. Current data strongly support further development of XZP-6924. The IND submission is expected in the second half of 2024. Citation Format: Zhihui Kan, Shujin Bai, Kelin Ma, Bo Chen, Benke Jiang, Feng Wang, Xifeng Ma, Dapeng Zhou, Chunmin Shi, Yanfang Nie, Yunling Wang, Ruxiao Liu, Jun Sun, Huimin Zhou, Mei Xu, Jiakui Li, Bin Liu. XZP-6924: A potent and highly selective USP1 inhibitor with the potential to improve efficacy and overcome resistance to PARP inhibitors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB269.