6VQL

CRYSTAL STRUCTURE OF INTERLEUKIN-1 RECEPTOR-ASSOCIATED KINASE 4 (IRAK4-WT) COMPLEX WITH A NICOTINAMIDE INHIBITOR

6VQL の概要

• エントリーDOI: 10.2210/pdb6vql/pdb
• 分子名称: Interleukin-1 receptor-associated kinase 4, 6-[(1,3-benzothiazol-6-yl)amino]-4-(cyclopropylamino)-N-[(2R)-2-fluoro-3-hydroxy-3-methylbutyl]pyridine-3-carboxamide, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: kinase, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 139768.94

構造登録者

Sack, J.S. (登録日: 2020-02-05, 公開日: 2020-06-24, 最終更新日: 2024-10-09)

主引用文献

Nair, S.,Kumar, S.R.,Paidi, V.R.,Sistla, R.,Kantheti, D.,Polimera, S.R.,Thangavel, S.,Mukherjee, A.J.,Das, M.,Bhide, R.S.,Pitts, W.J.,Murugesan, N.,Dudhgoankar, S.,Nagar, J.,Subramani, S.,Mazumder, D.,Carman, J.A.,Holloway, D.A.,Li, X.,Fereshteh, M.P.,Ruepp, S.,Palanisamy, K.,Mariappan, T.T.,Maddi, S.,Saxena, A.,Elzinga, P.,Chimalakonda, A.,Ruan, Q.,Ghosh, K.,Bose, S.,Sack, J.,Yan, C.,Kiefer, S.E.,Xie, D.,Newitt, J.A.,Saravanakumar, S.P.,Rampulla, R.A.,Barrish, J.C.,Carter, P.H.,Hynes Jr., J.
Optimization of Nicotinamides as Potent and Selective IRAK4 Inhibitors with Efficacy in a Murine Model of Psoriasis.
Acs Med.Chem.Lett., 11:1402-1409, 2020

PubMed Abstract: IRAK4 is an attractive therapeutic target for the treatment of inflammatory conditions. Structure guided optimization of a nicotinamide series of inhibitors has been expanded to explore the IRAK4 front pocket. This has resulted in the identification of compounds such as with improved potency and selectivity. Additionally demonstrated activity in a pharmacokinetics/pharmacodynamics (PK/PD) model. Further optimization efforts led to the identification of the highly kinome selective , which demonstrated a robust PD effect and efficacy in a TLR7 driven model of murine psoriasis.

PubMed: 32676146
DOI: 10.1021/acsmedchemlett.0c00082

実験手法

X-RAY DIFFRACTION (2.069 Å)