机构：[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.四川省肿瘤医院
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.
基金：
This work was supported by the Natural Science Foundation
of China (No. 81903445), the National Natural Science
Foundation of Shandong Province (Nos. ZR2023MB020,
ZR2022LSW015), the Taishan Scholars Program Young
Experts of Shandong Province, the Qilu Young Scholars
Program of Shandong University, and the Interdisciplinary
Innovative Project of Shandong University (No.
2020QNQT002)
第一作者机构：[1]School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, P.R. China.
通讯作者：
推荐引用方式(GB/T 7714)：
Zhu Chengchun,Zhao Haiyang,Yang Wenting,et al.Design, Synthesis and Antitumor Activity of a Novel Class of SHP2 Allosteric Inhibitors with a Furanyl Amide-Based Scaffold[J].Journal Of Medicinal Chemistry.2024,67(15):13305-13323.doi:10.1021/acs.jmedchem.4c01217.
APA：
Zhu Chengchun,Zhao Haiyang,Yang Wenting,Chen Kai,Liu Xiaoyu...&Yu Zhiyi.(2024).Design, Synthesis and Antitumor Activity of a Novel Class of SHP2 Allosteric Inhibitors with a Furanyl Amide-Based Scaffold.Journal Of Medicinal Chemistry,67,(15)
MLA：
Zhu Chengchun,et al."Design, Synthesis and Antitumor Activity of a Novel Class of SHP2 Allosteric Inhibitors with a Furanyl Amide-Based Scaffold".Journal Of Medicinal Chemistry 67..15(2024):13305-13323
医学