Title: Discovery of a small molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFR{alpha}, Kit, and Src kinases
Authors: Weisberg, Ellen ×
Choi, Hwan Geun
Ray, Arghya
Barrett, Rosemary
Zhang, Jianming
Sim, Taebo
Zhou, Wenjun
Seeliger, Markus
Cameron, Michael
Azam, Mohammed
Fletcher, Jonathan A
Debiec-Rychter, Maria
Mayeda, Mark
Moreno, Daisy
Kung, Andrew L
Janne, Pasi Antero
Khosravi-Far, Roya
Melo, Junia V
Manley, Paul
Adamia, Sophia
Wu, Catherine
Gray, Nathanael
Griffin, James D #
Issue Date: May-2010
Publisher: W.B. Saunders
Series Title: Blood vol:115 issue:21 pages:4206-4216
Abstract: Many clinically validated kinases, such as BCR-ABL, c-Kit, PDGFR and EGFR, become resistant to ATP-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 ATP competitive inhibitors, exemplified by HG-7-85-01, which is capable of inhibiting T315I- BCR-ABL (clinically observed in chronic myeloid leukemia (CML)), T670I-c-Kit (clinically observed in gastrointestinal stromal tumors (GIST)), and T674I/M-PDGFRalpha (clinically observed in hypereosinophilic syndrome (HEL)). HG-7-85-01 is unique amongst 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 mutants forms of several kinases of clinical relevance is an important step in the development of the next generation of tyrosine kinase inhibitors.
ISSN: 0006-4971
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Laboratory for Genetics of Malignant Disorders
× corresponding author
# (joint) last author

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