2. Academic Validation
  3. Discovery of Novel Alkynylbenzene Scaffold-Based PTPN2-Selective Degrader PD-305 with Exceptional Potency and In Vivo Efficacy

Discovery of Novel Alkynylbenzene Scaffold-Based PTPN2-Selective Degrader PD-305 with Exceptional Potency and In Vivo Efficacy

  • J Med Chem. 2026 May 28;69(10):11998-12019. doi: 10.1021/acs.jmedchem.5c03643.
Linghao Hu 1,  Liting Guo 1 2,  Mengxi Zhang 1 3,  Jingxun Wei 1 3,  Qi Huang 1,  Haowen Chen 1,  Ying Liu 1 4 5,  Xiaomin Xu 1 6,  Lei Xu 1,  Yubo Zhou 1 7,  Jia Li 1 2 7 8,  Mingliang Wang 1 4 3 5
Affiliations

Affiliations

  • 1 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China.
  • 2 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 3 School of Pharmaceutical Sciences, Southern Medical University, No.1023, South Shatai Road, Baiyun District, Guangzhou, Guangdong 510515, China.
  • 4 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 5 School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China.
  • 6 School of Pharmacy, Faculty of Medicine, Macau University of Science and Technology, Macau, Macau SAR 999078, China.
  • 7 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 8 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China.
PMID: 42132329 DOI: 10.1021/acs.jmedchem.5c03643
Abstract

Targeted degradation of PTPN2 is an attractive Cancer Immunotherapy strategy. However, unfavorable physicochemical properties limit the development of current PTPN2 degraders. In this study, using a ring-opening scaffold-hopping strategy, we identified a class of alkyne-containing PTPN2 ligands, which were subsequently employed for PROTAC design. Through optimizing linkers and CRBN ligands, we obtained PD-305, featuring a rigid linker and a naphtholactam-based ligand. PD-305 exhibits subnanomolar degradation potency (DC50 = 0.25 nM, 868-fold superior to the previously discovered PVD-06) and good subtype selectivity (PTPN2/PTPN1 selectivity >20-fold). Compared to previous PTPN2 degraders, it displays lower molecular weight, fewer hydrogen bond donors/acceptors, and a reduced cLogP. PD-305 exhibited nanomolar antiproliferation potency in the IFN-γ stimulated HT-29 cell line, nearly 80-fold more potent than the clinical candidate AC484. Moreover, it possessed excellent in vivo PTPN2 degradation potency and effectively suppressed tumor growth in mice. Collectively, PD-305 is a promising lead compound worthy of further study.

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