Format

Send to

Choose Destination
Cancer Lett. 2007 Jun 28;251(2):323-9. Epub 2007 Jan 19.

Structural basis for potent inhibition of the Aurora kinases and a T315I multi-drug resistant mutant form of Abl kinase by VX-680.

Author information

1
Vertex Pharmaceuticals (Europe) Ltd., 88 Milton Park, Abingdon, Oxfordshire, UK. graham_cheetham@vrtx.com

Abstract

The small molecule inhibitor of the Aurora-family of protein kinases VX-680 or MK-0457, demonstrates potent anti-cancer activity in multiple in vivo models and has recently entered phase II clinical trials. Although VX-680 shows a high degree of enzyme selectivity against multiple kinases, it unexpectedly inhibits both Flt-3 and Abl kinases at low nanomolar concentrations. Furthermore VX-680 potently inhibits Abl and the Imatinib resistant mutant (T315I) that is commonly expressed in refractory CML and ALL. We describe here the crystal structure of VX-680 bound to Aurora-A and show that this inhibitor exploits a centrally located hydrophobic pocket in the active site that is only present in an inactive or "closed" kinase conformation. A tight association of VX-680 with this hydrophobic pocket explains its high affinity for the Aurora kinases and also provides an explanation for its selectivity profile, including its ability to inhibit Abl and the Imatinib-resistant mutant (T315I).

PMID:
17240048
DOI:
10.1016/j.canlet.2006.12.004
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center