5E7R

Crystal structure of TL10-81 bound to TAK1-TAB1

Summary for 5E7R

• Entry DOI: 10.2210/pdb5e7r/pdb
• Descriptor: TAK1 kinase - TAB1 chimera fusion protein, 2-chloro-N-{2-[(5-chloro-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)oxy]phenyl}acetamide (3 entities in total)
• Functional Keywords: mitogen-activated protein kinase kinase kinase 7/tgf-beta-activated kinase 1 and map3k7-binding protein 1, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 35951.25

Authors

Gurbani, D.,Hunter, J.C.,Tan, L.,Chen, Z.,Westover, K.D. (deposition date: 2015-10-13, release date: 2016-09-21, Last modification date: 2024-10-16)

Primary citation

Tan, L.,Gurbani, D.,Weisberg, E.L.,Hunter, J.C.,Li, L.,Jones, D.S.,Ficarro, S.B.,Mowafy, S.,Tam, C.P.,Rao, S.,Du, G.,Griffin, J.D.,Sorger, P.K.,Marto, J.A.,Westover, K.D.,Gray, N.S.
Structure-guided development of covalent TAK1 inhibitors.
Bioorg. Med. Chem., 25:838-846, 2017

PubMed Abstract: TAK1 (transforming growth factor-β-activated kinase 1) is an essential intracellular mediator of cytokine and growth factor signaling and a potential therapeutic target for the treatment of immune diseases and cancer. Herein we report development of a series of 2,4-disubstituted pyrimidine covalent TAK1 inhibitors that target Cys174, a residue immediately adjacent to the 'DFG-motif' of the kinase activation loop. Co-crystal structures of TAK1 with candidate compounds enabled iterative rounds of structure-based design and biological testing to arrive at optimized compounds. Lead compounds such as 2 and 10 showed greater than 10-fold biochemical selectivity for TAK1 over the closely related kinases MEK1 and ERK1 which possess an equivalently positioned cysteine residue. These compounds are smaller, more easily synthesized, and exhibit a different spectrum of kinase selectivity relative to previously reported macrocyclic natural product TAK1 inhibitors such as 5Z-7-oxozeanol.

PubMed: 28011204
DOI: 10.1016/j.bmc.2016.11.035

Experimental method

X-RAY DIFFRACTION (2.11 Å)