Discovery of I-0436650, a potent and selective SHP2 allosteric inhibitor for the treatment of RAS driven solid tumors

Background: SHP2 (Src homology region 2-containing protein tyrosine phosphatase 2) is a target of interest for cancer therapy due to its key role in the regulation of RAS/MAPK signal transduction downstream of Receptor Tyrosine Kinases (RTKs). We report here the identification of I-0436650, a novel, highly potent, orally available SHP2 allosteric inhibitor, with potential for the treatment of tumors with dysregulated RTK/RAS/ERK signaling pathways. Material and Methods: High-throughput biological, biochemical and pharmacodynamic (PD) assays were used to inform Structure Activity Relationship studies which led to the identification of a chemical series of potent SHP2 inhibitors. Iterative optimization of physicochemical and pharmacological properties resulted in the identification of I-0436650, an orally available SHP2 inhibitor with excellent drug-like properties. The therapeutic potential of I-0436650 was tested in a series of ex vivo and in vivo experiments. Results: I-0436650 is a potent inhibitor of the SHP2 enzyme in vitro (IC50 = 5 nM) with a very slow koff rate (2.42E-05 1/s). When tested in cell line, it strongly inhibits pERK, a downstream marker of MAPK pathway activity, in a dose dependent manner. I-0436650 exhibits significant anti-proliferation activity against multiple RAS or EGFR mutant cancer cell lines alone and/or in combination with different FDA approved drugs. Further, I-0436650 effectively inhibits tumor growth in vivo in SHP2 dependent human xenograft models. Conclusions: I-0436650 is a potent, selective an orally available SHP2 inhibitor with potential for once-a-day dosing in humans. Of note, its predicted brain permeability in humans makes it a potential therapeutic agent against SHP2i responsive brain tumors and metastases. No conflict of interest.