Discovery of a small-molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFRα, Kit, and Src kinases: Novel type II inhibitor of gatekeeper mutants

Ellen Weisberg, Hwan Geun Choi, Arghya Ray, Rosemary Barrett, Jianming Zhang, Taebo Sim, Wenjun Zhou, Markus Seeliger, Michael Cameron, Mohammed Azam, Jonathan A. Fletcher, Maria Debiec-Rychter, Mark Mayeda, Daisy Moreno, Andrew L. Kung, Pasi Antero Janne, Roya Khosravi-Far, Junia V. Melo, Paul W. Manley, Sophia AdamiaCatherine Wu, Nathanael Gray, James D. Griffin

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55 Citations (Scopus)

Abstract

Many clinically validated kinases, such as BCR-ABL, c-Kit, PDGFR, and EGFR, become resistant to adenosine triphosphate-competitive inhibitors through mutation of the so-called gatekeeper amino acid from a threonine to a large hydrophobic amino acid, such as an isoleucine or methionine. We have developed a new class of adenosine triphosphate competitive inhibitors, exemplified by HG-7-85-01, which is capable of inhibiting T315I-BCR-ABL (clinically observed in chronic myeloid leukemia), T670I-c-Kit (clinically observed in gastrointestinal stromal tumors), and T674I/M-PDGFRα (clinically observed in hypereosinophilic syndrome). HG-7-85-01 is unique among all currently reported kinase inhibitors in having the ability to accommodate either a gatekeeper threonine, present in the wild-type forms of these kinases, or a large hydrophobic amino acid without becoming a promiscuous kinase inhibitor. The distinctive ability of HG-7-85-01 to simultaneously inhibit both wild-type and mutant forms of several kinases of clinical relevance is an important step in the development of the next generation of tyrosine kinase inhibitors.

Original languageEnglish
Pages (from-to)4206-4216
Number of pages11
JournalBlood
Volume115
Issue number21
DOIs
Publication statusPublished - 2010 May 27
Externally publishedYes

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ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Weisberg, E., Choi, H. G., Ray, A., Barrett, R., Zhang, J., Sim, T., Zhou, W., Seeliger, M., Cameron, M., Azam, M., Fletcher, J. A., Debiec-Rychter, M., Mayeda, M., Moreno, D., Kung, A. L., Janne, P. A., Khosravi-Far, R., Melo, J. V., Manley, P. W., ... Griffin, J. D. (2010). Discovery of a small-molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFRα, Kit, and Src kinases: Novel type II inhibitor of gatekeeper mutants. Blood, 115(21), 4206-4216. https://doi.org/10.1182/blood-2009-11-251751