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Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2860-5. doi: 10.1073/pnas.1120589109. Epub 2012 Feb 9.

STK33 kinase inhibitor BRD-8899 has no effect on KRAS-dependent cancer cell viability.

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  • 1Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA.

Abstract

Approximately 30% of human cancers harbor oncogenic gain-of-function mutations in KRAS. Despite interest in KRAS as a therapeutic target, direct blockade of KRAS function with small molecules has yet to be demonstrated. Based on experiments that lower mRNA levels of protein kinases, KRAS-dependent cancer cells were proposed to have a unique requirement for the serine/threonine kinase STK33. Thus, it was suggested that small-molecule inhibitors of STK33 might have therapeutic benefit in these cancers. Here, we describe the development of selective, low nanomolar inhibitors of STK33's kinase activity. The most potent and selective of these, BRD8899, failed to kill KRAS-dependent cells. While several explanations for this result exist, our data are most consistent with the view that inhibition of STK33's kinase activity does not represent a promising anti-KRAS therapeutic strategy.

PMID:
22323609
[PubMed - indexed for MEDLINE]
PMCID:
PMC3286931
Free PMC Article

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