Background: SHP2 is a non-receptor protein tyrosine phosphatase which functions as a convergent signaling node downstream of multiple receptor tyrosine kinases (RTKs), and upstream of RAS to promote oncogenic signaling and tumor growth. SHP2 also mediates PD-1 immune blockade of T cells by binding to the immune receptor tyrosine-based inhibitory motif (ITIM) and immune receptor tyrosine-based switch motif (ITSM) of PD-1. SHP2 has long been considered as a plausible oncology drug target not only as an oncoprotein, but also as an important immune modulator. However, for decades, SHP2 was thought to be "undruggable" due to difficulties in targeting its catalytic site. Recent discovery of allosteric site of SHP2 has inspired a novel approach for SHP2 targeting. Here we report the development of ICP-189, which is a potent, highly selective, and orally bioavailable allosteric inhibitor of SHP2, demonstrated robust efficacies in various in vitro and in vivo RAS/MAPK pathway-driven models as mono-therapeutic agent or in combination with other anti-cancer drugs.

Results: ICP-189 inhibits phosphatase activity of SHP2 with IC50 values < 5 nM. In a phosphatase profiling assay, ICP-189 efficiently inhibits the catalytic activity of SHP2, with no significant effects on 21 other tested tyrosine and serine/threonine phosphatases, indicating its high selectivity for SHP2. ICP-189 has demonstrated robust in vitro efficacies in a panel of tumor cell lines bearing activated RTK, RAS, NF1 loss-of-function, or BRAF class III mutations. It has also exhibited synergistic tumor killing effects in combination with EGFR, KRASG12C, MEK and CDK4/6 inhibitors. In a series of in vivo efficacy studies, ICP-189 treatment results in robust tumor growth control of MIA-PaCa-2, KYSE-520 and NCI-H358 xenografts. ICP-189 has also shown strong synergies in tumor killing when combined with MEK inhibitor trametinib, KRASG12C inhibitor sotorasib, EGFR inhibitor osimertinib in xenograft models; and when combined with anti-PD-1 antibody in EMT6 syngeneic tumors. The in vivo efficacy of ICP-189 is well accompanied by pharmacodynamic modulations, where ICP-189 exposure levels correlate with the inhibition of p-ERK and DUSP6 mRNA level in tumors. The pharmacokinetic parameters of ICP-189 are overall favorable, with high oral bioavailability. Nonclinical safety evaluations also exhibit acceptable drug tolerability in SD rats and Beagle dogs.

Conclusions: ICP-189 is a novel allosteric inhibitor of SHP2 with broad-spectrum anti-tumor activities as a single agent or in combination with other targeted or immune modulating anti-cancer therapeutics. ICP-189 is now in phase I clinical trial in China and United States.

Citation Format: Ruixia Liang, Yingxiang Gao, Fangfang Yang, Yingrui Han, Zuopeng Wang, Richard Liu, Charles Ying Wang, Jason Bin Zhang, Xiangyang Chen, Davy Xuesong Ouyang. Preclinical development of SHP2 allosteric inhibitor ICP-189. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4012.