Format

Send to

Choose Destination

See 1 citation:

Cell Rep. 2016 Feb 2;14(4):772-781. doi: 10.1016/j.celrep.2015.12.080. Epub 2016 Jan 14.

Kinase Inhibitor Profiling Reveals Unexpected Opportunities to Inhibit Disease-Associated Mutant Kinases.

Author information

1
Program in Cancer Biology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
2
Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
3
Reaction Biology Corporation, 1 Great Valley Parkway, Suite 2, Malvern, PA 19355, USA.
4
Program in Cancer Biology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA. Electronic address: jeffrey.peterson@fccc.edu.

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.

PMID:
26776524
PMCID:
PMC4740242
DOI:
10.1016/j.celrep.2015.12.080
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center