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Discovery of IRAK4 Inhibitors BAY1834845 (Zabedosertib) and BAY1830839 .

Ulrich BotheJudith GüntherReinhard NubbemeyerHolger SiebeneicherSven RingUlf BömerMichaele PetersAlexandra RauschKarsten DennerHerbert HimmelAndreas SutterIldiko TerebesiMartin LangeAntje M WengnerNicolas GuimondTobias ThalerJohannes PlatzekUwe EberspächerMartina SchäferHolger SteuberThomas M ZollnerAndreas SteinmeyerNicole Schmidt
Published in: Journal of medicinal chemistry (2024)
Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in innate inflammatory processes. Here, we describe the discovery of two clinical candidate IRAK4 inhibitors, BAY1834845 (zabedosertib) and BAY1830839 , starting from a high-throughput screening hit derived from Bayer's compound library. By exploiting binding site features distinct to IRAK4 using an in-house docking model, liabilities of the original hit could surprisingly be overcome to confer both candidates with a unique combination of good potency and selectivity. Favorable DMPK profiles and activity in animal inflammation models led to the selection of these two compounds for clinical development in patients.
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