Synthesis and biological evaluation of a tumor-selective degrader of PARP1

Bioorg Med Chem. 2022 Sep 1:69:116908. doi: 10.1016/j.bmc.2022.116908.

Chunlan Pu ¹, Shirui Wang ², Dan Luo ², Yuanyuan Liu ², Xinyu Ma ², Hongjia Zhang ², Su Yu ², Suke Lan ³, Qing Huang ², Rui Deng ², Xiang He ⁴, Rui Li ⁵

Affiliations

1 State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, China; Medical Research Center, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, The Second Chengdu Hospital Affiliated to Chongqing Medical University, Chengdu, Sichuan 610031, China.
2 State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, China.
3 College of Chemistry & Environment Protection Engineering, Southwest Minzu University, Chengdu, China.
4 Department of Obstetrics and Gynecology, West China Second Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Obstetrics & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, Sichuan University, Chengdu 610041, China.
5 State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, China. Electronic address: lirui@scu.edu.cn.

PMID: 35780655 DOI: 10.1016/j.bmc.2022.116908

Abstract

Poly (ADP-ribose) polymerase (PARP) inhibitors show potent antiproliferative activity in treatment with triple-negative breast Cancer (TNBC) when combined with chemotherapeutic drugs. However, the emergence of safety issues and drug-resistance of PARP inhibitors prompt us to search for new strategies. It was proved that Proteolysis Targeting Chimeras (PROTACs) is more effective than traditional small molecule which can induce target proteins degradation rather than inhibition. In this article, based on the Olaparib derivatives and Cereblon (CRBN) E3 Ligase ligands, a series of PARP1 degraders, with linkers bearing different length and type were designed and synthesized. Among them, compound LB23 showed efficacious antiproliferative activity in various human Cancer cells and can induce PARP1 protein degradation effectively. Moreover, LB23 showed 60-fold degradation selectivity in tumor cells with low degradation toxicity in normal cells. This study shows that the PROTAC tumor selectivity can be optimized by tuning the length and composition of the linker.

Keywords

Antitumor activity; Linker optimization; PARP1; PROTAC; Tumor selectivity.

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