7KXN

BTK1 SOAKED WITH COMPOUND 26

Summary for 7KXN

• Entry DOI: 10.2210/pdb7kxn/pdb
• Descriptor: Isoform BTK-C of Tyrosine-protein kinase BTK, 3-tert-butyl-N-[(1S)-6-{2-[5-methyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-1H-imidazo[4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,4-oxadiazole-5-carboxamide, DIMETHYL SULFOXIDE, ... (4 entities in total)
• Functional Keywords: transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 31902.76

Authors

Viacava Follis, A. (deposition date: 2020-12-04, release date: 2021-05-19, Last modification date: 2023-10-18)

Primary citation

Qiu, H.,Ali, Z.,Bender, A.,Caldwell, R.,Chen, Y.Y.,Fang, Z.,Gardberg, A.,Glaser, N.,Goettsche, A.,Goutopoulos, A.,Grenningloh, R.,Hanschke, B.,Head, J.,Johnson, T.,Jones, C.,Jones, R.,Kulkarni, S.,Maurer, C.,Morandi, F.,Neagu, C.,Poetzsch, S.,Potnick, J.,Schmidt, R.,Roe, K.,Viacava Follis, A.,Wing, C.,Zhu, X.,Sherer, B.
Discovery of potent and selective reversible Bruton's tyrosine kinase inhibitors.
Bioorg.Med.Chem., 40:116163-116163, 2021

PubMed Abstract: Bruton's tyrosine kinase (BTK) is a cytoplasmic, non-receptor tyrosine kinase member of the TEC family of tyrosine kinases. Pre-clinical and clinical data have shown that targeting BTK can be used for the treatment for B-cell disorders. Here we disclose the discovery of a novel imidazo[4,5-b]pyridine series of potent, selective reversible BTK inhibitors through a rational design approach. From a starting hit molecule 1, medicinal chemistry optimization led to the development of a lead compound 30, which exhibited 58 nM BTK inhibitory potency in human whole blood and high kinome selectivity. Additionally, the compound demonstrated favorable pharmacokinetics (PK), and showed potent dose-dependent efficacy in a rat CIA model.

PubMed: 33932711
DOI: 10.1016/j.bmc.2021.116163

Experimental method

X-RAY DIFFRACTION (1.34 Å)