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

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.

• Authors: Tuoping Luo, Kristina Masson, Jacob D Jaffe, Whitney Silkworth, Nathan T Ross, Christina A Scherer, Claudia Scholl, Stefan Fröhling, Steven A Carr, Andrew M Stern, Stuart L Schreiber, Todd R Golub
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 109 Issue 8 Pg. 2860-5 (Feb 21 2012) ISSN: 1091-6490 [Electronic] United States
• PMID: 22323609 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• BRD-8899
• Biomarkers, Tumor
• Isoquinolines
• KRAS protein, human
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins
• Small Molecule Libraries
• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
• STK26 protein, human
• Protein Serine-Threonine Kinases
• STK33 protein, human
• Extracellular Signal-Regulated MAP Kinases
• Proto-Oncogene Proteins p21(ras)
• ras Proteins
• fasudil

Topics

• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine (analogs & derivatives, pharmacology)
• Biological Assay
• Biomarkers, Tumor (metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• High-Throughput Screening Assays
• Humans
• Isoquinolines (chemistry, pharmacology)
• Neoplasms (enzymology, pathology)
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (chemistry, pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Proteomics
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins p21(ras)
• Small Molecule Libraries (pharmacology)
• ras Proteins (metabolism)