Discovery of a Novel Macrocyclic ATP Citrate Lyase Inhibitor.

Yongjun Zang, Luyang Tai, Yuanyang Hu, Yu Wang, Hongbin Sun, Xiaoan Wen, Haoliang Yuan, Liang Dai

Journal of chemical information and modeling 2022 Jun 27

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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.

Citation

Yongjun Zang, Luyang Tai, Yuanyang Hu, Yu Wang, Hongbin Sun, Xiaoan Wen, Haoliang Yuan, Liang Dai. Discovery of a Novel Macrocyclic ATP Citrate Lyase Inhibitor. Journal of chemical information and modeling. 2022 Jun 27;62(12):3123-3132