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

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.