Pyruvate carboxylase (PC) is an important anaplerotic enzyme that catalyzes the conversion of pyruvate to oxaloacetate (OAA) in a wide range of organisms. Studies have linked PC activity to a number of diseases and infections including certain types of cancer, type 2 diabetes, and listeriosis that are sustained as a result of aberrant or essential PC expression in cells. A structure-based project was initiated to develop chemical probes that will target the unique carboxytransferase domain of PC. These studies identified 2-hydroxycinnamic acids (1) and 3-heteroaryl-2-hydroxypropenoic acids (2) as inhibitors of PC. In addition, an in silico screening approach led to the discovery of a 2,4,5-imidazolidinedione inhibitor (3). Synthesis and evaluation of this lead inhibitor as well as other heteroaryl small molecules will be presented.

Synthesis and evaluation of inhibitors of pyruvate carboxylase

ACS Spring 2022

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