Unlocking the Potential of KO-947: A Potent ERK Inhibitor for MAPK Pathway-Disrupted Tumors

The RAS/RAF/MEK signaling pathway is a key factor in the development of cancer, especially in cases where there are mutations in RAS, BRAF, and NF1. Despite the availability of BRAF and MEK inhibitors for treating melanoma, the effectiveness of these treatments is often hindered by the development of resistance. ERK1/2 kinases, being the terminal component of the MAPK pathway, are less susceptible to the feedback mechanisms that can lead to resistance against RAF or MEK inhibitors.

A new compound, KO-947, has been identified as a potent and selective inhibitor of ERK1/2 kinases. It has been evaluated for its biochemical, cellular, and in vivo antitumor capabilities. KO-947 showed significant inhibitory effects on ERK with high selectivity and was effective in blocking the proliferation of tumor cells with MAPK pathway dysregulation, including those with BRAF, NRAS, or KRAS mutations.

The compound demonstrated an extended duration of action and high potency in cellular engagement, leading to sustained pathway inhibition both in vitro and in vivo. In xenograft models, KO-947 significantly suppressed ERK signaling and induced tumor regression in various cancer types, including melanoma, non-small cell lung cancer (NSCLC), and pancreatic cancer. The compound also showed effectiveness in patient-derived xenograft (PDX) models, with activity observed in colorectal, gastric, and cervical carcinomas, as well as in tumors with other MAPK pathway dysregulations.

KO-947's favorable pharmacokinetic properties allow for optimal antitumor activity with intermittent dosing, suggesting a potential therapeutic window with flexible administration. The findings suggest that KO-947 could be a promising treatment for tumors with dysregulation of the MAPK pathway.

Citation: Francis Burrows et al. "KO-947: A Potent ERK Inhibitor with Robust Preclinical Activity in MAPK Pathway Disrupted Tumors." Presented at the American Association for Cancer Research Annual Meeting, April 1-5, 2017, Washington, DC. Cancer Research, 2017; 77(13 Suppl): Abstract nr 5168. DOI: 10.1158/1538-7445.AM2017-5168.