Open AccessNS-187 (INNO-406), a Bcr-Abl/Lyn Dual Tyrosine Kinase Inhibitor
Author(s) -
Takeo Niwa,
Tetsuo Asaki,
Shinya Kimura
Publication year - 2007
Publication title -
analytical chemistry insights
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.406
H-Index - 17
ISSN - 1177-3901
DOI - 10.4137/117739010700200008
Subject(s) - lyn , dasatinib , imatinib , tyrosine kinase , cancer research , abl , imatinib mesylate , tyrosine kinase inhibitor , myeloid leukemia , tyrosine protein kinase csk , proto oncogene tyrosine protein kinase src , kinase , medicine , pharmacology , biology , chemistry , sh3 domain , signal transduction , microbiology and biotechnology , cancer
Protein kinases catalyze the transfer of the γ-phosphoryl group of adenosine triphosphate (ATP) to the hydroxyl groups of protein side chains, and they play critical roles in regulating cellular signal transduction and other biochemical processes. They are attractive targets for today's drug discovery and development, and many pharmaceutical companies are intensively developing various kinds of protein kinase inhibitors. A good example is the recent success with the Bcr-Abl tyrosine kinase inhibitor imatinib mesylate (Gleevec ™ ) in the treatment of chronic myeloid leukemia. Though imatinib has dramatically improved the treatment of Bcr-Abl-positive chronic myeloid leukemia, resistance is often found in patients with advanced-stage disease. Several mechanisms have been proposed to explain this resistance, including point mutations within the Abl kinase domain, amplification of the bcr-abl gene, overexpression of the corresponding mRNA, increased drug efflux mediated by P-glycoprotein, and activation of the Src-family kinase (SFK) Lyn. We set out to develop a novel drug whose affinity for Abl is higher than that of imatinib and whose specificity in inhibiting Lyn is higher than that of SFK/Abl inhibitors such as dasatinib (Sprycel ™ ) or bosutinib (SKI-606). Our work has led to the development of NS-187 (INNO-406), a novel Abl/Lyn dual tyrosine kinase inhibitor with clinical prospects. To provide an overview of how a selective kinase inhibitor has been developed, this review presents chemical-modification studies carried out with the guidance of molecular modeling, the structural basis for the high potency and selectivity of NS-187 based on the X-ray structure of the NS-187/Abl complex, and the biological profiling of NS-187, including site-directed mutagenesis experiments.