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

Mingfei Wu; Yiming Jiang; Daoming Zhang; Yiquan Wu; Yuyuan Jin; Tao Liu; Xinfei Mao; Hengyuan Yu; Tengfei Xu; Yong Chen; Wenhai Huang; Jinxin Che; Bo Zhang; Tao Liu; Nengming Lin; Xiaowu Dong

doi:10.1016/j.ejmech.2024.117062

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. Epub 2024 Nov 17.

Authors

Mingfei Wu¹, Yiming Jiang², Daoming Zhang², Yiquan Wu¹, Yuyuan Jin³, Tao Liu¹, Xinfei Mao¹, Hengyuan Yu⁴, Tengfei Xu⁴, Yong Chen⁴, Wenhai Huang³, Jinxin Che⁵, Bo Zhang⁶, Tao Liu⁷, Nengming Lin⁸, Xiaowu Dong⁹

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: [email protected].
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: [email protected].
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: [email protected].

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.

MeSH terms

Antineoplastic Agents* / chemical synthesis
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
BRCA1 Protein / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Colorectal Neoplasms* / drug therapy
Colorectal Neoplasms* / pathology
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Humans
Irinotecan / chemistry
Irinotecan / pharmacology
Molecular Structure
Poly (ADP-Ribose) Polymerase-1* / antagonists & inhibitors
Poly (ADP-Ribose) Polymerase-1* / metabolism
Poly(ADP-ribose) Polymerase Inhibitors / chemical synthesis
Poly(ADP-ribose) Polymerase Inhibitors / chemistry
Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
Proteolysis Targeting Chimera* / chemical synthesis
Proteolysis Targeting Chimera* / chemistry
Proteolysis Targeting Chimera* / pharmacology
Structure-Activity Relationship

Substances

Antineoplastic Agents
BRCA1 Protein
Irinotecan
PARP1 protein, human
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerase Inhibitors
Proteolysis Targeting Chimera