6CQ4

TBK1 in Complex with Cyclohexyl Analog of Amlexanox

Summary for 6CQ4

• Entry DOI: 10.2210/pdb6cq4/pdb
• Descriptor: Serine/threonine-protein kinase TBK1, 2-amino-7-(4,4-difluorocyclohexyl)-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylic acid (2 entities in total)
• Functional Keywords: tbk1, kinase, amlexanox, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 76400.26

Authors

Beyett, T.S.,Tesmer, J.J.G. (deposition date: 2018-03-14, release date: 2018-12-05, Last modification date: 2023-10-04)

Primary citation

Beyett, T.S.,Gan, X.,Reilly, S.M.,Gomez, A.V.,Chang, L.,Tesmer, J.J.G.,Saltiel, A.R.,Showalter, H.D.
Design, synthesis, and biological activity of substituted 2-amino-5-oxo-5H-chromeno[2,3-b]pyridine-3-carboxylic acid derivatives as inhibitors of the inflammatory kinases TBK1 and IKK epsilon for the treatment of obesity.
Bioorg. Med. Chem., 26:5443-5461, 2018

PubMed Abstract: The non-canonical IκB kinases TANK-binding kinase 1 (TBK1) and inhibitor of nuclear factor kappa-B kinase ε (IKKε) play a key role in insulin-independent pathways that promote energy storage and block adaptive energy expenditure during obesity. Utilizing docking calculations and the x-ray structure of TBK1 bound to amlexanox, an inhibitor of these kinases with modest potency, a series of analogues was synthesized to develop a structure activity relationship (SAR) around the A- and C-rings of the core scaffold. A strategy was developed wherein R and R A-ring substituents were incorporated late in the synthetic sequence by utilizing palladium-catalyzed cross-coupling reactions on appropriate bromo precursors. Analogues display IC values as low as 210 nM and reveal A-ring substituents that enhance selectivity toward either kinase. In cell assays, selected analogues display enhanced phosphorylation of p38 or TBK1 and elicited IL-6 secretion in 3T3-L1 adipocytes better than amlexanox. An analogue bearing a R cyclohexyl modification demonstrated robust IL-6 production in 3T3-L1 cells as well as a phosphorylation marker of efficacy and was tested in obese mice where it promoted serum IL-6 response, weight loss, and insulin sensitizing effects comparable to amlexanox. These studies provide impetus to expand the SAR around the amlexanox core toward uncovering analogues with development potential.

PubMed: 30270002
DOI: 10.1016/j.bmc.2018.09.020

Experimental method

X-RAY DIFFRACTION (3.2 Å)