2x81

Publication Abstract from PubMed

The Aurora kinases regulate multiple aspects of mitotic progression and their overexpression in diverse tumour types makes them appealing oncology targets. An intensive research effort over the last decade has led to the discovery of chemically distinct families of small molecule Aurora kinase inhibitors, many of which have demonstrated therapeutic potential in model systems. These agents are also important tools to help dissect signalling pathways that are orchestrated by Aurora kinases, and the anti-proliferative target of pan-Aurora inhibitors such as VX-680 has been validated using chemical genetic techniques. In many cases the non-specific nature of Aurora inhibitors towards unrelated kinases is well established, potentially broadening the spectrum of cancers to which these compounds might be applied. However, unambiguously demonstrating the molecular target(s) for clinical kinase inhibitors is an important challenge, and one that is absolutely critical for deciphering the molecular basis of compound specificity, resistance and efficacy. In this paper, we have investigated amino acid requirements for Aurora A sensitivity to the benzazepine-based Aurora inhibitor MLN8054 and the close analog MLN8237, a second-generation compound that is in phase II clinical trials. A crystallographic analysis facilitated the design and biochemical investigation of a panel of resistant Aurora A mutants, a subset of which were then selected as candidate drug-resistance targets for further evaluation. Using inducible human cell lines, we show that cells expressing near-physiological levels of a functional, but partially drug-resistant, Aurora A T217D mutant survive in the presence of MLN8054 or MLN8237, authenticating Aurora A as a critical anti-proliferative target of these compounds.

Drug-resistant Aurora A mutants for cellular target validation of the small molecule kinase inhibitors MLN8054 and MLN8237.,Sloane D, Trikic M, Chu ML, Lamers M, Mason C, Mueller I, Savory W, Williams DH, Eyers PA ACS Chem Biol. 2010 Apr 28. PMID:20426425^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.