Abstract PR002: Nimbolide targets RNF114 to induce the trapping of PARP1 and synthetic lethality in BRCA-mutated cancer

Abstract

Abstract Despite the tremendous success of PARP1 inhibitors (PARPi) for the treatment of BRCA mut tumors, intrinsic and acquired resistance to PARPi remains a critical challenge in the clinic. This is, at least in part, due to the incomplete understanding of the mechanism of action (MoA) of PARPi. Recent studies from both our lab and others have pointed to PARP1 trapping as a key determinant of the anticancer effects of PARP1 inhibitors (PARPi). However, the molecular underpinnings of PARP1 trapping are poorly understood. Here we performed a proteomics-based chromatin relocalization screen, and identified RNF114, as a PARylation-dependent, E3 ubiquitin ligase involved in DNA damage response. Upon sensing genotoxicity, RNF114 was recruited, in a PAR-dependent manner, to DNA lesions, where it targeted PARP1 for degradation. The blockade of this pathway interfered with the removal of PARP1 from DNA lesions, leading to profound PARP1 trapping. A unique feature of this pathway is its druggability. We showed that a natural product, nimbolide, inhibited the E3 ligase activity of RNF114 and thus caused PARP1 trapping. However, unlike conventional PARPi, nimbolide treatment induced the trapping of both PARP1 and PARylation-dependent DNA repair factors. The unique mechaism of action of nimbolide translated into its superior cytotoxicity against BRCA mut cancer cells, compared to regular PARPi. It is also able to potentially overcome intrinsic and acquired resistance to PARPi, both in vitro and in vivo. In collaboration with Dr. Tian Qin, we recently performed the first total synthesis of nimbolide via a pharmacophore-directed, late-stage coupling strategy. Using this method, we have obtained a large panel of novel nimbolide analogs with improved activity and drug-like properties. We have further garnered key SAR (structure-activity relationship) insights into nimbolide. These results point to the exciting possibility of translating nimbolide analogs into novel PARP1-targeting agents for the treatment of BRCA mut cancers. Citation Format: Peng Li, Yuanli Zhen, Chiho Kim, Zhengshuai Liu, Jianwei Hao, Heping Deng, Hejun Deng, Min Zhou, Xu-Dong Wang, Tian Qin, Yonghao Yu. Nimbolide targets RNF114 to induce the trapping of PARP1 and synthetic lethality in BRCA-mutated cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr PR002.