Genetic and pharmacologic evidence has shown that SHP2, a non-receptor protein tyrosine phosphatase (PTP) and scaffold protein encoded by the PTPN11 gene, is a convergent signal transduction node that integrates growth factor signals from multiple receptors to promote activation of RAS and its downstream effectors. Guided by structural insights from in-house x-ray crystallographic data, we describe a strategy aimed at the identification of a highly potent and selective allosteric SHP2 inhibitor series with exposure profiles commensurate with once daily oral dosing. This led to the discovery of RMC-4550 which exhibited a high quality, drug-like preclinical profile. The presentation will outline the structure and synthesis of RMC-4550, detailed x-ray crystal structure guided SAR, physicochemical property controlled optimization, detailed in vitro and in vivo ADMET assessment, alongside in vivo PKPD and efficacy data in preclinical xenograft models.

RMC-4550: An allosteric inhibitor optimized for in vivo studies of SHP2

255th National Meeting (2018)

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