Discovery of a Novel Macrocyclic ATP Citrate Lyase Inhibitor,Journal of Chemical Information and Modeling

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Discovery of a Novel Macrocyclic ATP Citrate Lyase Inhibitor
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2022-06-09 , DOI: 10.1021/acs.jcim.2c00345
Yongjun Zang ₁ , Luyang Tai ₁ , Yuanyang Hu ₁ , Yu Wang ₁ , Hongbin Sun ₁ , Xiaoan Wen ₁ , Haoliang Yuan ₁ , Liang Dai ₁

Affiliation

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 (T_1/2 = 3.36 min), the metabolic stability of 2 in HLMs (T_1/2 = 531.22 min) was significantly improved. All of these results characterized 2 as a promising lead compound worthy of further study

中文翻译：

一种新型大环 ATP 柠檬酸裂解酶抑制剂的发现

ATP柠檬酸裂解酶（ACLY）是一种重要的代谢酶，参与脂肪酸和胆固醇的合成。ACLY 的抑制被认为是一种有前途的治疗各种代谢疾病和许多恶性肿瘤的策略。在这项研究中，一种新型的大环化合物2已被鉴定为一种有效的 ACLY 抑制剂，具有基于NDI - 091143的构象限制的“闭环”策略。它显示出与阳性对照相当的有效 ACLY 抑制活性和结合亲和力。此外，与阳性对照（T _1/2 = 3.36 min）相比，HLMs中2的代谢稳定性（T _1/2= 531.22 分钟）显着改善。所有这些结果都将2描述为值得进一步研究的有前途的先导化合物

更新日期：2022-06-09

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