Journal
BIOCHEMICAL PHARMACOLOGY
Volume 80, Issue 5, Pages 683-689Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2010.03.012
Keywords
p21-activated kinases; Organometallic; Kinase inhibitors; Breast cancer; Neurofibromatosis
Categories
Funding
- Children's Tumor Foundation
- Department of Defense Neurofibromatosis
- NATIONAL CANCER INSTITUTE [F32CA123752] Funding Source: NIH RePORTER
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The p21-activated kinases (PAKs), immediate downstream effectors of the small G-proteins of the Rac/cdc42 family, are critical mediators of signaling pathways regulating cellular behaviors and as such, have been implicated in pathological conditions including cancer. Recent studies have validated the requirement for PAKs in promoting tumorigenesis in breast carcinoma and neurofibromatosis. Thus, there has been considerable interest in the development of inhibitors to the PAKs, as biological markers and leads for the development of therapeutics. While initial approaches were based on screening for competitive organic inhibitors, more recent efforts have focused on the identification of allosteric inhibitors, organometallic ATP-competitive inhibitors and the use of PAK1/inhibitor crystal structures for inhibitor optimization. This has led to the identification of highly selective and potent inhibitors, which will serve as a basis for further development of inhibitors for therapeutic applications. (C) 2010 Elsevier Inc. All rights reserved.
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