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

Tuoping Luo1, Kristina Masson, Jacob D Jaffe

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

Proceedings of the National Academy of Sciences of the United States of America
|February 11, 2012
PubMed

Insights

Researchers developed STK33 kinase inhibitors for KRAS-dependent cancers. The most potent inhibitor, BRD8899, did not kill cancer cells, suggesting STK33 inhibition is not a viable anti-KRAS therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Approximately 30% of human cancers have mutations in KRAS, a key therapeutic target.
  • KRAS-dependent cancer cells were hypothesized to require the serine/threonine kinase STK33.
  • Small-molecule inhibitors of STK33 were proposed as a potential cancer therapy.

Purpose of the Study:

  • To develop selective small-molecule inhibitors of STK33 kinase activity.
  • To evaluate the therapeutic potential of STK33 inhibition in KRAS-dependent cancers.

Main Methods:

  • Development of selective, low nanomolar inhibitors of STK33.
  • Testing the most potent inhibitor, BRD8899, in KRAS-dependent cancer cells.

Main Results:

  • Selective STK33 inhibitors, including BRD8899, were successfully developed.
  • BRD8899 failed to inhibit the growth or survival of KRAS-dependent cancer cells.
  • The data suggest STK33 kinase activity is not essential for KRAS-dependent cancer cell viability.

Conclusions:

  • Inhibition of STK33 kinase activity is unlikely to be an effective therapeutic strategy for KRAS-dependent cancers.
  • Targeting STK33 is not a promising approach for anti-KRAS cancer therapies.

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