Carboxylic Acid Derivatives of Amlexanox Display Enhanced Potency toward TBK1 and IKKε and Reveal Mechanisms for Selective Inhibition.

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 IκB kinase ε (IKKε) 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 i

SUBMITTER: Beyett TS 

PROVIDER: S-EPMC6128810 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature