16691-52-4Relevant academic research and scientific papers
A comparative study of fragment screening methods on the p38α kinase: New methods, new insights
Pollack, Scott J.,Beyer, Kim S.,Lock, Christopher,Mueller, Ilka,Sheppard, David,Lipkin, Mike,Hardick, David,Blurton, Peter,Leonard, Philip M.,Hubbard, Paul A.,Todd, Daniel,Richardson, Christine M.,Ahrens, Thomas,Baader, Manuel,Hafenbradl, Doris O.,Hilyard, Kate,Buerli, Roland W.
, p. 677 - 687 (2012/07/16)
The stress-activated kinase p38α was used to evaluate a fragment-based drug discovery approach using the BioFocus fragment library. Compounds were screened by surface plasmon resonance (SPR) on a Biacore T100 against p38α and two selectivity targets. A sub-set of our library was the focus of detailed follow-up analyses that included hit confirmation, affinity determination on 24 confirmed, selective hits and competition assays of these hits with respect to a known ATP binding site inhibitor. In addition, functional activity against p38α was assessed in a biochemical assay using a mobility shift platform (LC3000, Caliper LifeSciences). A selection of fragments was also evaluated using fluorescence lifetime (FLEXYTE) and microscale thermophoresis (Nanotemper) technologies. A good correlation between the data for the different assays was found. Crystal structures were solved for four of the small molecules complexed to p38α. Interestingly, as determined both by X-ray analysis and SPR competition experiments, three of the complexes involved the fragment at the ATP binding site, while the fourth compound bound in a distal site that may offer potential as a novel drug target site. A first round of optimization around the remotely bound fragment has led to the identification of a series of triazole-containing compounds. This approach could form the basis for developing novel and active p38α inhibitors. More broadly, it illustrates the power of combining a range of biophysical and biochemical techniques to the discovery of fragments that facilitate the development of novel modulators of kinase and other drug targets.
