2. Academic Validation
  3. Discovery of a potent PARP1 PROTAC as a chemosensitizer for the treatment of colorectal cancer

Discovery of a potent PARP1 PROTAC as a chemosensitizer for the treatment of colorectal cancer

  • Eur J Med Chem. 2025 Jan 15:282:117062. doi: 10.1016/j.ejmech.2024.117062.
Mingfei Wu 1,  Yiming Jiang 2,  Daoming Zhang 2,  Yiquan Wu 1,  Yuyuan Jin 3,  Tao Liu 1,  Xinfei Mao 1,  Hengyuan Yu 4,  Tengfei Xu 4,  Yong Chen 4,  Wenhai Huang 3,  Jinxin Che 5,  Bo Zhang 6,  Tao Liu 7,  Nengming Lin 8,  Xiaowu Dong 9
Affiliations

Affiliations

  • 1 Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • 2 Research Center for Clinical Pharmacy, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • 3 Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, 310058, China.
  • 4 Institute of Modern Chinese Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • 5 Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310009, China.
  • 6 Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310024, China; Westlake Laboratory of Life Sciences and Biomedicine of Zhejiang Province, Hangzhou, 310024, China.
  • 7 Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310009, China. Electronic address: lt601@zju.edu.cn.
  • 8 Research Center for Clinical Pharmacy, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310024, China; Westlake Laboratory of Life Sciences and Biomedicine of Zhejiang Province, Hangzhou, 310024, China. Electronic address: lnm1013@zju.edu.cn.
  • 9 Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; Department of Pharmacy, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China; State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310009, China. Electronic address: dongxw@zju.edu.cn.
PMID: 39602992 DOI: 10.1016/j.ejmech.2024.117062
Abstract

Given the vulnerability of colorectal Cancer (CRC) patients could not obtain a sustained benefit from chemotherapy, combination therapy is frequently employed as a treatment strategy. Targeting PARP1 blockade exhibit specific toxicity towards tumor cells with BRCA1 or BRCA2 mutations through synthetic lethality. This study focuses on developing a series of potent PROTACs targeting PARP1 in order to enhance the sensitivity of CRC cells with BRCA1 or BRCA2 mutations to chemotherapy. Compound C6, obtained based on precise structural optimization of the linker, has been shown to effectively degrade PARP1 with a DC50 value of 58.14 nM. Furthermore, C6 significantly increased the cytotoxic efficacy of SN-38, an active metabolite of Irinotecan, in BRCA-mutated CRC cells, achieving a favorable combination index (CI) of 0.487. In conclusion, this research underscores the potential benefits of employing a combination therapy that utilizes PAPRP1 degrader C6 alongside Irinotecan for CRC patients harboring BRCA mutations in CRC.

Keywords

Chemosensitizer; Chemotherapy; Colorectal cancer; PARP1; PROTAC.

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