2. Academic Validation
  3. Design, Synthesis and Antitumor Activity of a Novel Class of SHP2 Allosteric Inhibitors with a Furanyl Amide-Based Scaffold

Design, Synthesis and Antitumor Activity of a Novel Class of SHP2 Allosteric Inhibitors with a Furanyl Amide-Based Scaffold

  • J Med Chem. 2024 Aug 8;67(15):13305-13323. doi: 10.1021/acs.jmedchem.4c01217.
Chengchun Zhu 1,  Haiyang Zhao 2 3,  Wenting Yang 1,  Kai Chen 4,  Xiaoyu Liu 4,  Yan Yu 1,  Rui Li 5,  Ruirong Tan 3,  Zhiyi Yu 1
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, P.R. China.
  • 2 School of Life Science and Engineering, Southwest University of Science and Technology, No. 59, Middle Section of Qinglong Avenue, Mianyang 621010, P.R. China.
  • 3 Center for Organoids and Translational Pharmacology, Translational Chinese Medicine Key Laboratory of Sichuan Province, Sichuan Institute for Translational Chinese Medicine, Sichuan Academy of Chinese Medicine Sciences, Chengdu 610041, P.R. China.
  • 4 Center for New Drug Evaluation, Shandong Academy of Pharmaceutical Sciences, Jinan 250000, P.R. China.
  • 5 Sichuan Cancer Hospital and Institute, School of Medicine, University of Electronic Science and Technology of China, No. 55, Section 4, South Renmin Road, Chengdu 610041, P.R. China.
PMID: 39066713 DOI: 10.1021/acs.jmedchem.4c01217
Abstract

SHP2 plays a critical role in modulating tumor growth and PD-1-related signaling pathway, thereby serving as an attractive antitumor target. To date, no antitumor drugs targeting SHP2 have been approved, and hence, the search of SHP2 inhibitors with new chemical scaffolds is urgently needed. Herein, we developed a novel SHP2 allosteric inhibitor SDUY038 with a furanyl amide scaffold, demonstrating potent binding affinity (KD = 0.29 μM), enzymatic activity (IC50 = 1.2 μM) and similar binding interactions to SHP099. At the cellular level, SDUY038 exhibited pan-antitumor activity (IC50 = 7-24 μM) by suppressing PERK expression. Furthermore, SDUY038 significantly inhibited tumor growth in both xenograft and Organoid models. Additionally, SDUY038 displayed acceptable bioavailability (F = 14%) and half-life time (t1/2 = 3.95 h). Conclusively, this study introduces the furanyl amide scaffold as a novel class of SHP2 allosteric inhibitors, offering promising lead compounds for further development of new antitumor therapies targeting SHP2.

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