Discovery And Characterization Of Az6197, A Potent And Selective Erk1/2 Inhibitor

The RAS/MAPK pathway is a major driver in oncogenesis and is dysregulated in approximately 30% of human cancers, primarily by mutations in BRAF or RAS genes. The extracellular-signal-regulated kinases (ERK1 and ERK2) serve as key central nodes within this pathway. The feasibility of targeting the RAS/MAPK pathway has been demonstrated by the initial positive clinical responses observed to BRAF and MEK inhibitors in BRAF V600E/K metastatic melanoma; however, resistance frequently develops by reactivation of the RAS/MAPK pathway. Direct targeting of ERK1/2 may provide another therapeutic option in tumors with mutations in BRAF or RAS genes and, importantly, may overcome acquired resistance to RAF and MEK inhibitors where RAS/MAPK pathway reactivation has occurred, such as relapsed BRAF V600E/K melanoma. Here we describe the discovery and characterization of compound 35 (Ward et al., J Med Chem 2017 27;60), also known as AZ6197. AZ6197 is a highly potent and selective inhibitor of ERK1 and ERK2, with IC 50 of Citation Format: Vikki Flemington, Iain Simpson, Emma Davies, David Robinson, Nicola Lindsay, Lyndsey Hanson, Philip Hopcroft, Michael Tonge, Karen Roberts, Richard Ward. Discovery and characterization of AZ6197, a potent and selective ERK1/2 inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B156.