6BOD

TBK1 in complex with ethyl ester analog of amlexanox

6BOD の概要

• エントリーDOI: 10.2210/pdb6bod/pdb
• 分子名称: Serine/threonine-protein kinase TBK1, ethyl 2-amino-5-oxo-7-(propan-2-yl)-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylate (2 entities in total)
• 機能のキーワード: tbk1, kinase, amlexanox, obesity, diabetes, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 76352.27

構造登録者

Beyett, T.S.,Tesmer, J.J.G. (登録日: 2017-11-19, 公開日: 2018-09-26, 最終更新日: 2023-10-04)

主引用文献

Beyett, T.S.,Gan, X.,Reilly, S.M.,Chang, L.,Gomez, A.V.,Saltiel, A.R.,Showalter, H.D.,Tesmer, J.J.G.
Carboxylic Acid Derivatives of Amlexanox Display Enhanced Potency toward TBK1 and IKKepsilonand Reveal Mechanisms for Selective Inhibition.
Mol. Pharmacol., 94:1210-1219, 2018

PubMed Abstract: Chronic low-grade inflammation is a hallmark of obesity, which is a risk factor for the development of type 2 diabetes. The drug amlexanox inhibits IB kinase (IKK) and TANK binding kinase 1 (TBK1) to promote energy expenditure and improve insulin sensitivity. Clinical studies have demonstrated efficacy in a subset of diabetic patients with underlying adipose tissue inflammation, albeit with moderate potency, necessitating the need for improved analogs. Herein we report crystal structures of TBK1 in complex with amlexanox and a series of analogs that modify its carboxylic acid moiety. Removal of the carboxylic acid or mutation of the adjacent Thr156 residue significantly reduces potency toward TBK1, whereas conversion to a short amide or ester nearly abolishes the inhibitory effects. IKK is less affected by these modifications, possibly due to variation in its hinge that allows for increased conformational plasticity. Installation of a tetrazole carboxylic acid bioisostere improved potency to 200 and 400 nM toward IKK and TBK1, respectively. Despite improvements in the in vitro potency, no analog produced a greater response in adipocytes than amlexanox, perhaps because of altered absorption and distribution. The structure-activity relationships and cocrystal structures described herein will aid in future structure-guided inhibitor development using the amlexanox pharmacophore for the treatment of obesity and type 2 diabetes.

PubMed: 30082428
DOI: 10.1124/mol.118.112185

実験手法

X-RAY DIFFRACTION (3.197 Å)