Identification of a Novel, Potent, and Orally Bioavailable Guanidine-Based SHP2 Allosteric Inhibitor from Virtual Screening and Rational Structural Optimization for the Treatment of KRAS Mutant Cancers

作者：Qiangqiang Hou, Wenhua Jiang, Wenqiang Li, Chenyang Huang, Kexin Yang, Xiaoyu Chen, Mengchen Huang, Chengxia Shu, Guangmei Luo, Haopeng Sun, Qian Chu, Xiaoxing Wu · 发表于：Journal of Medicinal Chemistry · 年份：2023 · DOI：10.1021/acs.jmedchem.3c00992 · 被引用次数：13 · 研究领域：Protein Tyrosine Phosphatases、Galectins and Cancer Biology、Peptidase Inhibition and Analysis

Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) is a highly attractive therapeutic target for treating Kirsten rat sarcoma viral oncogene (KRAS) mutant cancers. In this work, a series of guanidine-based SHP2 allosteric inhibitors were discovered via virtual screening and rational structural optimization. Notably, lead compound 23 with potent SHP2 inhibitory activity (IC 50 = 17.7 nM) effectively inhibited the proliferation, migration, and invasion of MIA PaCa-2 pancreatic cancer cells. Furthermore, compound 23 featured great in vivo pharmacokinetic properties (AUC po = 4320 nM·h; F = 66.3%) and exhibited significant antitumor efficacy in the MIA PaCa-2 xenograft mouse model. This demonstrates that compound 23 is a potential lead compound for the development of SHP2 allosteric inhibitors to treat KRAS mutant cancers. Moreover, these guanidine-based scaffolds may provide an opportunity to mitigate the potential safety risks of the alkyl amine motif predominately incorporated in current SHP2 allosteric inhibitors.