Abstract 4788: Discovery of potent and selective inhibitors of ERK1/2 with a unique mechanism of action

Abstract

Abstract Activation of the RAS/MAPK pathway occurs via a cascade of protein phosphorylation events which culminate in the phosphorylation & activation of ERK 1/2. Aberrant activation of this pathway has been demonstrated in several human tumor types. Inhibitors of this pathway in clinical development target upstream kinases, BRAF or MEK. Only a few ERK 1/2 has been reported. The goal of the ERK program was to develop a targeted therapy that is guided by a clear patient selection / responder identification plan based on BRAF and K/NRAS mutations. Utilizing an affinity based high-throughput screening strategy (ALIS), we discover a novel class of small molecule ERK 1/2 inhibitors. Optimization of this chemical series led to the discovery of SCH 772984, which is highly selective ERK1/2 inhibitor, inhibiting cell proliferation selectively in tumor cell lines with an activated MAPK pathway and causes significant tumor regression in vivo in BRAF & RAS mutant xenograft models. Based on insights gained through crystallographic analysis, SCH 772984 and related compounds have a unique ERK binding mode which results in a novel dual mechanism of inhibition, blocking ERK phosphorylation by MEK as well as inhibiting ERK kinase activity. This novel mechanism enables the use of ERK phosphorylation as a target engagement biomarker. Biological differences between pathway inhibition at the level or ERK vs. inhibition of upstream kinases are being examined. The SAR and crystal structures of this series ERK inhibitors will be reported. Citation Format: Yongqi Deng, Ahmed Samatar, Gerald Shipps, Alan Cooper, Brian Long, Donnar Carr, Li Xiao, Alan Hruza, Tong Wang, Liang Zhu, Yang Nan, Mehul Patel, Kiran Muppalla, Hugh Zhu, Babu Sobhana Boga, Xiaolei Gao. Discovery of potent and selective inhibitors of ERK1/2 with a unique mechanism of action. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4788.