TY - JOUR
T1 - Discovery of a small-molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFRα, Kit, and Src kinases
T2 - Novel type II inhibitor of gatekeeper mutants
AU - Weisberg, Ellen
AU - Choi, Hwan Geun
AU - Ray, Arghya
AU - Barrett, Rosemary
AU - Zhang, Jianming
AU - Sim, Taebo
AU - Zhou, Wenjun
AU - Seeliger, Markus
AU - Cameron, Michael
AU - Azam, Mohammed
AU - Fletcher, Jonathan A.
AU - Debiec-Rychter, Maria
AU - Mayeda, Mark
AU - Moreno, Daisy
AU - Kung, Andrew L.
AU - Janne, Pasi Antero
AU - Khosravi-Far, Roya
AU - Melo, Junia V.
AU - Manley, Paul W.
AU - Adamia, Sophia
AU - Wu, Catherine
AU - Gray, Nathanael
AU - Griffin, James D.
PY - 2010/5/27
Y1 - 2010/5/27
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=77953636478&partnerID=8YFLogxK
U2 - 10.1182/blood-2009-11-251751
DO - 10.1182/blood-2009-11-251751
M3 - Article
C2 - 20299508
AN - SCOPUS:77953636478
SN - 0006-4971
VL - 115
SP - 4206
EP - 4216
JO - Blood
JF - Blood
IS - 21
ER -