AZD0364 is a potent and selective ERK1/2 inhibitor which enhances anti-tumour activity in KRAS mutant tumour models when combined with the MEK inhibitor selumetinib.

The RAS-regulated RAF-MEK1/2-ERK1/2 (RAS/MAPK) signalling pathway is a major driver in oncogenesis and is frequently dysregulated in human cancers, primarily by mutations in BRAF or RAS genes. The clinical benefit of inhibitors of this pathway as single agents has only been realized in BRAF mutant melanoma, with limited effect of single agent pathway inhibitors in KRAS mutant tumours. Combined inhibition of multiple nodes within this pathway, such as MEK1/2 and ERK1/2, may be necessary to effectively suppress pathway signalling in KRAS mutant tumours and achieve meaningful clinical benefit. Here we report the discovery and characterization of AZD0364, a novel, reversible, ATP-competitive ERK1/2 inhibitor with high potency and kinase selectivity. In vitro, AZD0364 treatment resulted in inhibition of proximal and distal biomarkers and reduced proliferation in sensitive BRAF mutant and KRAS mutant cell lines. In multiple in vivo xenograft models, AZD0364 showed dose and time-dependent modulation of ERK1/2-dependent signalling biomarkers resulting in tumour regression in sensitive BRAF and KRAS mutant xenografts. We demonstrate that AZD0364 in combination with the MEK1/2 inhibitor selumetinib (AZD6244, ARRY142886) enhances efficacy in KRAS mutant preclinical models that are moderately sensitive or resistant to MEK1/2 inhibition. This combination results in deeper and more durable suppression of the RAS/MAPK signalling pathway that is not achievable with single agent treatment. The AZD0364 and selumetinib combination also results in significant tumour regressions in multiple KRAS mutant xenograft models. The combination of ERK1/2 and MEK1/2 inhibition thereby represents a viable clinical approach to target KRAS mutant tumours.