7YAZ

Crystal structure of ZAK in complex with compound YH-186

Summary for 7YAZ

• Entry DOI: 10.2210/pdb7yaz/pdb
• Descriptor: Mitogen-activated protein kinase kinase kinase MLT, ~{N}-[2,4-bis(fluoranyl)-3-[4-[3-[(3~{S})-1-propanoylpyrrolidin-3-yl]oxy-1~{H}-pyrazolo[3,4-b]pyridin-5-yl]-1,2,3-triazol-1-yl]phenyl]-3-phenyl-benzenesulfonamide (3 entities in total)
• Functional Keywords: zak, inhibitor, yh-186, structural protein, structural protein-inhibitor complex, structural protein/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 36008.19

Authors

Kong, L.L.,Yun, C.H. (deposition date: 2022-06-28, release date: 2023-08-09, Last modification date: 2024-11-20)

Primary citation

Zhou, Y.,Yu, H.,Vind, A.C.,Kong, L.,Liu, Y.,Song, X.,Tu, Z.,Yun, C.,Smaill, J.B.,Zhang, Q.W.,Ding, K.,Bekker-Jensen, S.,Lu, X.
Rational Design of Covalent Kinase Inhibitors by an Integrated Computational Workflow (Kin-Cov).
J.Med.Chem., 66:7405-7420, 2023

PubMed Abstract: Covalent kinase inhibitors (CKIs) hold great promise for drug development. However, examples of computationally guided design of CKIs are still scarce. Here, we present an integrated computational workflow (Kin-Cov) for rational design of CKIs. The design of the first covalent leucine-zipper and sterile-α motif kinase (ZAK) inhibitor was presented as an example to showcase the power of computational workflow for CKI design. The two representative compounds, and , inhibited ZAK kinase with half-maximal inhibitory concentration (IC) values of 9.1 and 11.5 nM, respectively. Compound displayed an excellent ZAK target specificity in Kinome profiling against 378 wild-type kinases. Structural biology and cell-based Western blot washout assays validated the irreversible binding characteristics of the compounds. Our study presents a rational approach for the design of CKIs based on the reactivity and accessibility of nucleophilic amino acid residues in a kinase. The workflow is generalizable and can be applied to facilitate CKI-based drug design.

PubMed: 37220641
DOI: 10.1021/acs.jmedchem.3c00088

Experimental method

X-RAY DIFFRACTION (2.54 Å)