Abstract 1176: Preclinical characterization of the pharmacokinetic-pharmacodynamics-efficacy relationship of novel allosteric SHP2 inhibitors
Authors: Minying Pu, Laura R. La Bonte, Stan Spence, Kathy Hsiao, Shumei Liu, Brant Firestone, Ping Wang, Pascal D. Fortin, Ying-Nan P. Chen, Matthew J. LaMarche, Matthew J. Meyer
Journal: Cancer Research (2017)

Abstract SHP2 is a non-receptor protein tyrosine phosphatase downstream of receptor tyrosine kinases (RTK). Mutations yielding constitutive activation of SHP2 primarily lead to activation of the MAPK pathway and have been found in multiple tumor types. These observations make SHP2 a potentially promising therapeutic target for the treatment of cancers with RTK dependence. Recently, a novel allosteric mechanism of SHP2 inhibition was identified where the autoinhibited form of SHP2 is stabilized via small molecule binding. Herein we describe efforts to characterize the pharmacokinetic (PK)/pharmacodynamic (PD)/efficacy relationship of orally bioavailable novel allosteric SHP2 inhibitors. Single dose PK/PD studies were conducted in nude mice engrafted with the EGFR amplified esophageal squamous cell carcinoma cell line, KYSE520. The allosteric SHP2 inhibitor SHP099 achieved time and dose dependent increases in plasma concentrations and concomitant reductions in tumor pERK that could be described by an Emax model. Tumor pERK levels were reduced by 50 to 70% when SHP099 unbound plasma concentrations exceeded the in vitro cellular PD IC50, suggesting that exposure above this threshold was required for pathway inhibition in vivo. A second allosteric SHP2 inhibitor, SHP065, was also profiled in vivo and yielded data consistent with this hypothesis. Two additional allosteric SHP2 inhibitors (SHP156, SHP393) that achieved unbound plasma concentrations approximating their cellular IC50s failed to modulate tumor pERK. The totality of these data support the hypothesis that unbound plasma concentrations in excess of the cellular IC50 is required for allosteric SHP2 inhibitors to inhibit the MAPK pathway in vivo. We further demonstrated that SHP099 achieves dose dependent inhibition of KYSE520 tumor xenograft growth in nude mice. Integration of the antitumor efficacy data and pERK inhibition data revealed a direct linear relationship between tumor growth inhibition and the fraction of time between dosing intervals in which pERK is inhibited by at least 50%. To test this model, SHP099 PK data from nude rats was applied to the Emax model and the resulting predicted PD responses were applied to the PD/efficacy model to predict SHP099 anti-tumor efficacy in nude rats. Data generated from a SHP099 KYSE520 efficacy study in nude rats demonstrated that the exposure/response model was remarkably robust. Doses of 8 mg/kg qd, 25 mg/kg qd, or 75 mg/kg q2d yielded observed T/C of 70, 14, and 18%, respectively; versus a model predicted T/C of 75, 6, and 6%, respectively. In summary, we describe for the first time successful efforts to characterize the PK/PD/efficacy relationship of novel allosteric SHP2 inhibitors. These exposure/response models served as a basis for further allosteric SHP2 inhibitor drug discovery efforts and begin to inform rational approaches to dose and schedule selection in clinic. Citation Format: Minying Pu, Laura R. La Bonte, Stan Spence, Kathy Hsiao, Shumei Liu, Brant Firestone, Ping Wang, Pascal D. Fortin, Ying-Nan P. Chen, Matthew J. LaMarche, Matthew J. Meyer. Preclinical characterization of the pharmacokinetic-pharmacodynamics-efficacy relationship of novel allosteric SHP2 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1176. doi:10.1158/1538-7445.AM2017-1176