Novel azabicyclic series of potent SHP2 allosteric inhibitors

Abstract

The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, is a critical component of the RAS/RAF/MEK/ERK signaling pathway, functioning upstream of RAS to promote oncogenic signaling and tumor growth. As part of a drug discovery program aimed at obtaining novel allosteric SHP2 inhibitors, a series of original azabicyclic compounds was identified. Extensive preliminary SAR around the novel bicyclic basic moiety (left-hand side) and the heteroaryl portion (right-hand side) yielded a highly potent series of SHP2 inhibitors with demonstrated cellular potency (pERK inhibition, as downstream marker of MAPK pathway activity) as well as antiproliferative activity in a KYSE-520 cancer cell line. Further optimization of the physicochemical properties and reduction of in vitro off-target liabilities, including hERG inhibition, led to the identification of a unique series of SHP2 inhibitors with strong potential for development in efficacy studies using appropriate animal models.

Keywords: Allosteric inhibition; Azabicyclo[4.1.0]heptane; Oncology; Phosphatase; SHP2; pERK.