title: Kinase Inhibitor Profiling Reveals Unexpected Opportunities to Inhibit Disease-Associated Mutant Kinases.
abstract: Small-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 PDGFRα 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.
authors.affiliation: Program in Cancer Biology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
authors.forename: Krisna C
authors.initials: KC
authors.lastname: Duong-Ly
authors.affiliation: Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
authors.forename: Karthik
authors.initials: K
authors.lastname: Devarajan
authors.affiliation: Reaction Biology Corporation, 1 Great Valley Parkway, Suite 2, Malvern, PA 19355, USA.
authors.forename: Shuguang
authors.initials: S
authors.lastname: Liang
authors.affiliation: Reaction Biology Corporation, 1 Great Valley Parkway, Suite 2, Malvern, PA 19355, USA.
authors.forename: Kurumi Y
authors.initials: KY
authors.lastname: Horiuchi
authors.affiliation: Reaction Biology Corporation, 1 Great Valley Parkway, Suite 2, Malvern, PA 19355, USA.
authors.forename: Yuren
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Reaction Biology Corporation, 1 Great Valley Parkway, Suite 2, Malvern, PA 19355, USA.
authors.forename: Haiching
authors.initials: H
authors.lastname: Ma
authors.affiliation: Program in Cancer Biology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA. Electronic address: jeffrey.peterson@fccc.edu.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Peterson
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D055808:Drug Discovery / Q000379:methods; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009154:Mutation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D066246:ErbB Receptors; D020796:Receptor, Platelet-Derived Growth Factor alpha