Abstract B156: Discovery and characterization of AZ6197, a potent and selective ERK1/2 inhibitor
Authors: Flemington Vikki , Simpson Iain , Davies Emma , Robinson David , Lindsay Nicola , Hanson Lyndsey , Hopcroft Philip , Tonge Michael , Roberts Karen , Ward Richard 
Published: August 2018

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 IC50 of &lt;1nM in biochemical assays. AZ6197 reduces cellular phospho-p90RSK1 levels in BRAF and RAS mutant cancer cell lines and inhibits proliferation of cancer cell lines exhibiting dysregulation of RAS/MAPK pathway signaling, including cell lines with mutations in BRAF, NRAS, or KRAS. AZ6197 is also active in multiple BRAF- and MEK- inhibitor resistant A375 melanoma cell lines, which have acquired a range of mutations that reactivate the RAS/MAPK pathway. In tumor xenograft models, AZ6197 reduces the pharmacodynamic (PD) biomarkers phospho-p90RSK1 and phospho-FRA1 in tumors in line with compound exposure levels, and induces significant tumor regression in the KRAS mutant NSCLC Calu 6 xenograft model. AZ6197 can be combined safely and effectively with the MEK1/2 inhibitor selumetinib in KRAS mutant NSCLC xenograft models, and this simultaneous targeting of MEK and ERK leads to synergistic tumor regressions being observed in multiple xenografts. In summary, AZ6197 is a potent and selective ERK1/2 inhibitor with activity in cell lines and tumor xenograft models with RAS/MAPK pathway activation. AZ6197 also has significant activity in BRAF mutant melanoma cell lines in which resistance to RAF and MEK inhibitors is due to the acquisition of NRAS and MEK1 mutations. Combination treatment of AZ6197 and the MEK1/2 inhibitor selumetinib drives synergistic tumor regression in multiple KRAS mutant xenograft models.

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.