当前位置： SCI文献检索 > EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Development of dual inhibitors targeting pyruvate dehydrogenase kinases and human lactate dehydrogenase A: High-throughput virtual screening, synthesis and biological validation.

Development of dual inhibitors targeting pyruvate dehydrogenase kinases and human lactate dehydrogenase A: High-throughput virtual screening, synthesis and biological validation.

Abstract：

:Most cancer cells feature an altered glucose metabolism from oxidative phosphorylation to cytoplasmic glycolysis. Pyruvate dehydrogenase kinases (PDKs) and lactate dehydrogenase A (LDHA) play crucial roles in promotion of glycolysis, thus the inhibition of both enzymes is considered a promising strategy for developing of anticancer therapeutics. Herein, we describe the first discovery of series novel dual inhibitors targeting PDKs and LDHA. We identified 6 hits from a library database containing 485465 compounds through a high-throughput virtual screening assay. Hit-to-lead optimization enabled us to discover two compounds, namely 20e and 20k, which inhibited PDKs with IC50 values of 0.8, and 1.6 μM, respectively, and inhibited LDHA with IC50 values of 0.15 and 0.7 μM, respectively. Meanwhile, the two compounds reduced A549 cell proliferation with EC50 values of 13.2, and 15.7 μM. Furthermore, 20e and 20k decreased the lactate formation, and increased oxygen consumption, suggesting the two compounds modulated the glucose metabolic pathways in cancer cells.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Xiang S,Huang D,He Q,Li J,Tam KY,Zhang SL,He Y

doi

10.1016/j.ejmech.2020.112579

subject

Has Abstract

pub_date

2020-10-01 00:00:00

pages

112579

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(20)30551-1

journal_volume

203

pub_type

杂志文章

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