当前位置: X-MOL 学术Eur. J. Med. Chem. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Discovery of novel human lactate dehydrogenase inhibitors: Structure-based virtual screening studies and biological assessment
European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2022-07-14 , DOI: 10.1016/j.ejmech.2022.114605
Laura Di Magno 1 , Antonio Coluccia 2 , Marianna Bufano 2 , Silvia Ripa 1 , Giuseppe La Regina 2 , Marianna Nalli 2 , Fiorella Di Pastena 1 , Gianluca Canettieri 1 , Romano Silvestri 2 , Luigi Frati 3
Affiliation  

Most cancer cells switch their metabolism from mitochondrial oxidative phosphorylation to aerobic glycolysis to generate ATP and precursors for the biosynthesis of key macromolecules. The aerobic conversion of pyruvate to lactate, coupled to oxidation of the nicotinamide cofactor, is a primary hallmark of cancer and is catalyzed by lactate dehydrogenase (LDH), a central effector of this pathological reprogrammed metabolism. Hence, inhibition of LDH is a potential new promising therapeutic approach for cancer. In the search for new LDH inhibitors, we carried out a structure-based virtual screening campaign. Here, we report the identification of a novel specific LDH inhibitor, the pyridazine derivative 18 (RS6212), that exhibits potent anticancer activity within the micromolar range in multiple cancer cell lines and synergizes with complex I inhibition in the suppression of tumor growth. Altogether, our data support the conclusion that compound 18 deserves to be further investigated as a starting point for the development of LDH inhibitors and for novel anticancer strategies based on the targeting of key metabolic steps.



中文翻译:

新型人乳酸脱氢酶抑制剂的发现:基于结构的虚拟筛选研究和生物学评估

大多数癌细胞将其代谢从线粒体氧化磷酸化转变为有氧糖酵解,以产生 ATP 和用于生物合成关键大分子的前体。丙酮酸向乳酸的有氧转化,再加上烟酰胺辅因子的氧化,是癌症的主要标志,由乳酸脱氢酶 (LDH) 催化,乳酸脱氢酶 (LDH) 是这种病理性重编程代谢的中心效应物。因此,抑制LDH是一种潜在的新的有前途的癌症治疗方法。在寻找新的 LDH 抑制剂时,我们开展了基于结构的虚拟筛选活动。在这里,我们报告了一种新型特异性 LDH 抑制剂哒嗪衍生物18的鉴定(RS6212),在多种癌细胞系中表现出微摩尔范围内的有效抗癌活性,并与复合物 I 抑制协同抑制肿瘤生长。总之,我们的数据支持以下结论:化合物18值得进一步研究,作为开发 LDH 抑制剂和基于关键代谢步骤靶向的新型抗癌策略的起点。

更新日期:2022-07-19
down
wechat
bug