Successful Screening of Large Encoded Combinatorial Libraries Leading to the Discovery of Novel p38 MAP Kinase Inhibitors

Title: Successful Screening of Large Encoded Combinatorial Libraries Leading to the Discovery of Novel p38 MAP Kinase Inhibitors

Volume: 9 Issue: 5

Author(s): Axel Metzger, David J. Diller, Tsung H. Lin, Ian Henderson and Maria L. Webb

Affiliation:

Keywords: Combinatorial libraries, kinase selectivity, kinase inhibitors, p38 kinase, combinatorial synthesis

Abstract: Screening of more than 2 million compounds comprising 41 distinct encoded combinatorial libraries revealed a novel structural class of p38 mitogen-activated protein (MAP) kinase inhibitors. The methodology used for screening large encoded combinatorial libraries combined with the statistical interpretation of screening results is described. A strong preference for a particular triaminotriazine aniline amide was discovered based on biological activity observed in the screening campaign. Additional screening of a focused follow-up combinatorial library yielded data expanding the unique combinatorial SAR and emphasizing an extraordinary preference for this particular building block and structural class. The preference is further highlighted when the p38 inhibitor data set is compared to data obtained for a panel of other kinases.

Cite this article as:

Metzger Axel, Diller J. David, Lin H. Tsung, Henderson Ian and Webb L. Maria, Successful Screening of Large Encoded Combinatorial Libraries Leading to the Discovery of Novel p38 MAP Kinase Inhibitors, Combinatorial Chemistry & High Throughput Screening 2006; 9 (5) . https://dx.doi.org/10.2174/138620706777452384