2. Academic Validation
  3. Rational DESIGN and Structure-activity relationship study of novel JOSD2 inhibitor against colorectal cancer

Rational DESIGN and Structure-activity relationship study of novel JOSD2 inhibitor against colorectal cancer

  • Bioorg Chem. 2025 Nov:166:109022. doi: 10.1016/j.bioorg.2025.109022.
Pengwei Liu 1,  Yiting Guo 1,  Runqiu Guo 1,  Tao Yuan 1,  Yuhan Lai 1,  Hong Zhu 1,  Yuchen Zhang 2,  Qiaojun He 3,  Chenghao Pan 4
Affiliations

Affiliations

  • 1 Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou 310018, PR China.; Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
  • 2 Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou 310018, PR China.; Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.. Electronic address: 21737076@zju.edu.cn.
  • 3 Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou 310018, PR China.; Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.. Electronic address: qiaojunhe@zju.edu.cn.
  • 4 Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou 310018, PR China.; Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.. Electronic address: 11919003@zju.edu.cn.
PMID: 41092805 DOI: 10.1016/j.bioorg.2025.109022
Abstract

Deubiquitinases (DUBs) catalyze the removal of ubiquitin moieties from substrate proteins, playing pivotal roles in regulating protein homeostasis. Targeting DUBs with small-molecule inhibitors to induce substrate protein degradation has emerged as a compelling strategy for addressing traditionally "undruggable" targets. Notably, multiple DUB inhibitors have advanced to preclinical and clinical stages. In our preliminary research, we discovered that the deubiquitinating enzyme Josephin domain-containing 2 (JOSD2) played a significant role in the development and progression of colorectal Cancer (CRC). In this study, we identified a novel hit compound 1 targeting the JOSD2 through high-throughput screening of an internal compound library. Subsequently, guided by structure-activity relationship (SAR) analysis, compound 31 was synthesized, a JOSD2 inhibitor featuring a cyanamide warhead that selectively engaged the catalytic cysteine residue. Preliminary biological mechanism studies revealed a covalent binding mode between compound 31 and JOSD2. Further mechanistic studies have shown that 31 could induce the downregulation of KRAS protein expression in HCT116 cells, thereby exerting proliferation inhibitory activity (IC50 = 0.93 ± 0.01 μM). Collectively, our research identified that targeting JOSD2 with small-molecule inhibitors could represent a potential future therapeutic strategy for CRC.

Keywords

Covalent inhibitors; Deubiquitinating enzyme JOSD2; Drug development; Protein homeostasis.

Figures
Products