Description
KO947 is an ERK inhibitor (IC
50 = <50 nM for ERK2). It is greater than 50-fold selective for ERK over a panel of 450 kinases. KO947 reduces phosphorylation of the ERK target p90 ribosomal S6 kinase (RSK) in A375 cancer cells containing constitutively active B-RAF
V600E with an IC
50 value of less than 250 nM. It inhibits proliferation of A375 cells, as well as mutant K-Ras-expressing HCT116 and H358 cancer cell lines (IC
50s = 50-250 nM for all).
Uses
KO-947 is a potent and selective inhibitor of ERK1/2 kinases with potential utility in MAPK pathway dysregulated tumors.
in vivo
In cell-line derived xenograft studies, KO-947 profoundly suppresses ERK signaling for up to five days after a single dose and induces regressions in RAS- and RAF-mutant melanoma, NSCLC and pancreatic cancer models on administration schedules ranging from daily to weekly. Intermittent dosing enables comparable antitumor activity at reduced dose-intensity[1].
References
[1] Burrows F, et al. KO-947, a potent ERK inhibitor with robust preclinical single agent activity in MAPK pathway dysregulated tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5168. doi:10.1158/1538-7445.AM2017-5168.
