Discovery of 5-Aryl-2,4-diaminopyrimidine Compounds as Potent and Selective IRAK4 Inhibitors.

ABSTRACT: IRAK4 kinase plays a key role in TLR/IL-1R signaling pathways that regulate innate immune responses, and if uncontrolled, it is responsible for various inflammatory disorders. By high-throughput screening (HTS) and hit-to-lead optimization, compounds with a 5-aryl-2,4-diaminopyrimidine core structure have been identified as potent IRAK4 inhibitors. A cocrystal structure of IRAK4 protein with an early lead molecule helped with understanding the structure-activity relationship and the design of the new compounds. Initial HTS hits from this series of compounds were also found to inhibit TAK1 kinase, which would cause liver toxicity and potentially bone marrow failure. Optimization of this series resulted in improved selectivity over TAK1 kinase. The TAK1 selectivity was found to be closely as

SUBMITTER: Chen Y 

PROVIDER: S-EPMC9014513 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature