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Kinase Inhibitor Profiling Reveals Unexpected Opportunities to Inhibit Disease-Associated Mutant Kinases
Cell Rep. 2016 Feb 2;14(4) :772-81
PMID: 26776524 PMCID: PMC4740242 URL: http://www.ncbi.nlm.nih.gov/pubmed/26776524
AbstractSmall-molecule kinase inhibitors have typically been designed to inhibit wild-type kinases rather than the mutant forms that frequently arise in diseases such as cancer. Mutations can have serious clinical implications by increasing kinase catalytic activity or conferring therapeutic resistance. To identify opportunities to repurpose inhibitors against disease-associated mutant kinases, we conducted a large-scale functional screen of 183 known kinase inhibitors against 76 recombinant mutant kinases. The results revealed lead compounds with activity against clinically important mutant kinases, including ALK, LRRK2, RET, and EGFR, as well as unexpected opportunities for repurposing FDA-approved kinase inhibitors as leads for additional indications. Furthermore, using T674I PDGFRalpha as an example, we show how single-dose screening data can provide predictive structure-activity data to guide subsequent inhibitor optimization. This study provides a resource for the development of inhibitors against numerous disease-associated mutant kinases and illustrates the potential of unbiased profiling as an approach to compound-centric inhibitor development.
NotesDuong-Ly, Krisna C Devarajan, Karthik Liang, Shuguang Horiuchi, Kurumi Y Wang, Yuren Ma, Haiching Peterson, Jeffrey R eng P30 CA006927/CA/NCI NIH HHS/ R01 GM083025/GM/NIGMS NIH HHS/ T32 CA009035/CA/NCI NIH HHS/ 2016/01/19 06:00 Cell Rep. 2016 Feb 2;14(4):772-81. doi: 10.1016/j.celrep.2015.12.080. Epub 2016 Jan 14.