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

作者：Wei**erg 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 W; Adamia Sophia; Wu Catherine; Gray Nathanael; Griffin James D

来源：Blood, 2010, 115(21): 4206-4216.

DOI：10.1182/blood-2009-11-251751

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-PDGFR alpha (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. (Blood. 2010; 115(21): 4206-4216)

• 出版日期2010-5-27
• 单位河北医科大学