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

  • J Med Chem. 2023 Oct 12;66(19):13646-13664. doi: 10.1021/acs.jmedchem.3c00992.
Qiangqiang Hou  1  2 ,  Wenhua Jiang  1  2 ,  Wenqiang Li  1  2 ,  Chenyang Huang  1  2 ,  Kexin Yang  1  2 ,  Xiaoyu Chen  1  2 ,  Mengchen Huang  1  2 ,  Chengxia Shu  1  2 ,  Guangmei Luo  1  2 ,  Haopeng Sun  1  3  4 ,  Qian Chu  1  3 ,  Xiaoxing Wu  1  2
Affiliations
  • 1. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 2. Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China.
  • 3. Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
  • 4. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
PMID: 37754066 DOI: 10.1021/acs.jmedchem.3c00992
Abstract

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 (IC50 = 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 (AUCpo = 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.

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