8W3X

Crystal structure of IRAK4 in complex with compound 6

This is a non-PDB format compatible entry.

Summary for 8W3X

• Entry DOI: 10.2210/pdb8w3x/pdb
• Descriptor: Interleukin-1 receptor-associated kinase 4, 7-ethoxy-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide (3 entities in total)
• Functional Keywords: interleukin-1 receptor-associated kinase 4, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 147653.48

Authors

Han, S.,Knafels, J.D. (deposition date: 2024-02-22, release date: 2024-05-01, Last modification date: 2024-11-13)

Primary citation

Wright, S.W.,Farley, K.A.,Han, S.,Knafels, J.D.,Lee, K.L.
In Retrospect: Root-Cause Analysis of Structure-Activity Relationships in IRAK4 Inhibitor Zimlovisertib (PF-06650833).
Acs Med.Chem.Lett., 15:540-545, 2024

PubMed Abstract: In this paper, we disclose insights on the root causes of three structure-activity relationship (SAR) observations encountered in the discovery of the IRAK4 inhibitor Zimlovisertib (PF-06650833). The first is a nonlinear potency SAR encountered with the isoquinoline ether substituent, the second is a potency enhancement introduced by fluorine substitution on the lactam, and the third is a slight potency preference for all- (2,3,4) stereochemistry in the fluorine-substituted lactam. We present new data that help to inform us of the origins of these unexpected SAR trends.

PubMed: 38628800
DOI: 10.1021/acsmedchemlett.4c00036

Experimental method

X-RAY DIFFRACTION (1.765 Å)