6VQL

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

Summary for 6VQL

• Entry DOI: 10.2210/pdb6vql/pdb
• Descriptor: 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)
• Functional Keywords: kinase, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 139768.94

Authors

Sack, J.S. (deposition date: 2020-02-05, release date: 2020-06-24, Last modification date: 2024-10-09)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.069 Å)