Structure-Based Discovery of Spiro Sulfonamide Scaffolds as PDK Inhibitors

Abstract

Inflammatory bowel disease (IBD) is associated with dysregulated CD4⁺ T-cell metabolism, including excessive Th17 activation and impaired Treg function. Pyruvate dehydrogenase kinases (PDKs), particularly PDK1 and PDK4, regulate T-cell immunometabolism by controlling pyruvate dehydrogenase activity and ER–mitochondria Ca²⁺ coupling. Based on a known lipoamide-site pharmacophore, we designed PDK inhibitors incorporating the (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionamide scaffold. SAR studies identified a spiro-based benzenesulfonamide chemotype with strong inhibitory activity. Among the series, compound 23 was the most potent, showing IC₅₀ values of 42.91 nM and 41.63 nM for PDK1 and PDK4, respectively, with minimal inhibition of PDK2 and PDK3. Compound 23 also exhibited favorable pharmacokinetic properties, negligible hERG inhibition, and no mutagenicity or detectable toxicity in preliminary studies. These findings support compound 23 as a promising PDK inhibitor capable of correcting T-cell .immunometabolic dysfunction in IBD.