Abstract 1735: Discovery of novel and selective reversible inhibitors of EGFR containing the T790M drug resistance mutation with activity in vitro and in vivo

Abstract

Abstract Activating mutations in the epidermal growth factor receptor (EGFR) characterize a subset of non-small cell lung cancers (NSCLC) with exquisite sensitivity to tyrosine kinase inhibitors like erlotinib or gefitinib. However, after an initial dramatic response, patients harboring these mutations progress within 8-14 months on therapy. In approximately 60% of patients, the resistance to TKIs is associated with the acquisition of a secondary mutation within the EGFR kinase domain. The mutation in the kinase domain leads to the substitution of a bulky methionine for threonine at position 790 (T790M) also referred to as the gatekeeper residue. Using structure based-design we identified and optimized a series of non-covalent, and highly selective pyridinyl-aminopyrimidine inhibitors of EGFR containing the T790M drug resistant mutation that spared the wild-type EGFR enzyme. These pyridinyl-aminopyrimidine compounds potently inhibited phosphorylation of T790M containing EGFR in enzymatic assays and cell based assays. Strong inhibition of enzyme activity resulted in anti-proliferative activity in H1975 and PC9 erlotinib resistant cells but treatment with these molecules did not affect cell lines containing wild-type EGFR. Moreover, oral dosing of mice bearing either H1975 or PC9_erlotinib resistant xenograft tumors resulted in robust inhibition of tumor growth that was accompanied by profound and dose-dependent inhibition of EGFR activity as well as downstream signaling molecules such as ERK1/2 and AKT. These results suggest that these pyridinyl-aminopyrimidine inhibitors have the potential to benefit NSCLC patients who have developed resistance to first-generation EGFR inhibitors due to the acquisition of the T790M mutation, without the skin rash and gastrointestinal toxicity associated with wild-type EGFR inhibition. *EJH and GS contributed equally to this work. Citation Format: Gabriele Schaefer, Emily J. Hanan, Emily Chan, Lily Shao, Yuan Chen, Jamie Knight, Robert L. Yauch, Stephen Schmidt, Steven Sideris, Shiva Malek, Timothy P. Heffron. Discovery of novel and selective reversible inhibitors of EGFR containing the T790M drug resistance mutation with activity in vitro and in vivo. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1735. doi:10.1158/1538-7445.AM2014-1735