Abstract LB-005: Allosteric SHP2 phosphatase inhibition: Multiple mechanisms and chemotypes

Protein tyrosine phosphatase SHP2 is an oncoprotein associated with cancer as well as a potential immune modulator due to its role in the programmed cell death PD-L1/PD-1 pathway. Small molecule inhibition of SHP2 has been widely investigated including our previous reports describing SHP099, which binds to a tunnel-like allosteric binding site. To broaden our approach to allosteric inhibition of SHP2, we conducted additional hit finding, evaluation, and structure-based scaffold morphing. These studies led to the identification of multiple, potent inhibitor chemotypes, an additional and distinct allosteric binding site, and the identification of SHP394, an orally efficacious inhibitor of SHP2 with improved potency and enhanced pharmacokinetic properties. Overall, this work improves upon our previously described allosteric inhibitors, and exemplifies and extends the range of permissible chemical templates that inhibit SHP2 via the allosteric mechanism. Citation Format: Matthew J. LaMarche, Jeff Bagdanoff, Mike Acker, Ying-Nan Chen, Homan Chan, Michael Dore, Brant Firestone, Michelle Fodor, Jorge Garcia-Fortanet, Murphy Hentemann, Mitsunori Kato, Robert Koenig, Laura La Bonte, Shumei Liu, Movarid Mohseni, Rukundo Ntaganda, Patrick Sarver, Troy Smith, Martin Sendzik, Travis Stams, Stan Spence, Chris Towler, Hongyun Wang, Ping Wang, Sarah Williams, Zhouliang Chen, Huaixiang Hao, Gang Liu, Chen Liu, Eric McNeill, Bing Yu. Allosteric SHP2 phosphatase inhibition: Multiple mechanisms and chemotypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-005.