Successful screening of large encoded combinatorial libraries leading to the discovery of novel p38 MAP kinase inhibitors.
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.
Metzger
Axel
A
Pharmacopeia Drug Discovery Inc., Princeton, NJ 08543-5350, USA. ametzger@pcop.com
Diller
David J
DJ
Lin
Tsung H
TH
Henderson
Ian
I
Webb
Maria L
ML
D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008956:Models, Chemical; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; D048051:p38 Mitogen-Activated Protein Kinases