Discovery of a Novel Macrocyclic ATP Citrate Lyase Inhibitor
Yong-Jun Zang, Luyang Tai, Yuan-Yang Hu, Yu Wang, Hongbin Sun, Xiaoan Wen, Haoliang Yuan, Liang Dai
Abstract
ATP citrate lyase (ACLY) is an important metabolic enzyme involved in the synthesis of fatty acid and cholesterol. The inhibition of ACLY is considered as a promising therapeutic strategy for various metabolic diseases and numerous malignancies. In this study, a novel macrocyclic compound 2 has been identified as a potent ACLY inhibitor with the “ring closing” strategy for conformational restriction based on NDI-091143. It showed potent ACLY inhibitory activity and binding affinity comparable to the positive control. Furthermore, compared with the positive control (T1/2 = 3.36 min), the metabolic stability of 2 in HLMs (T1/2 = 531.22 min) was significantly improved. All of these results characterized 2 as a promising lead compound worthy of further study