Synthesis, biological evaluation and structure-activity relationship of novel dichloroacetophenones targeting pyruvate dehydrogenase kinases with potent anticancer activity

Pyruvate dehydrogenase kinases (PDKs) are promising therapeutic targets that have received increasing attentions in cancer metabolism. In this paper, we report the synthesis and biological evaluation of a series of novel dichloroacetophenones as potent PDKs inhibitors. Structure-activity relationship analysis enabled us to identify a potent compound 6u, which inhibited PDKs with an EC50 value of 0.09 mu M, and reduced various cancer cells proliferation with IC50 values ranging from 1.1 to 3.8 mu M, while show weak effect against non-cancerous L02 cell (IC50 > 10 mu M). In the A375 xenograft model, 6u displayed an obvious antitumor activity at a dose of 5 mg/kg, but with no negative effect to the mice weight. Molecular docking suggested that 6u formed direct hydrogen bond interactions with Ser75 and Gln61 in PDK1, and meanwhile the aniline skeleton in 6u was sandwiched by the conserved hydrophobic residues Phe78 and Phe65, which contribute to the biochemical activity improvement. Moreover, 6u induced A375 cell apoptosis and cell arrest in G1 phase, and inhibited cancer cell migration. In addition, 6u altered glucose metabolic pathway in A375 cell by decreasing lactate formation and increasing ROS production and OCR consumption, which could serve as a potential modulator to reprogram the glycolysis pathway in cancer cell. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

This study reported a series of novel dichloroacetophenones as potent PDKs inhibitors, with compound 6u showing significant anti-proliferative effects on various cancer cells. In mouse models, 6u demonstrated potent antitumor activity without negative impact on body weight. The compound was also found to induce cancer cell apoptosis, arrest cell cycle progression, inhibit cell migration, and alter glucose metabolic pathways in cancer cells, showing potential as a modulator for reprogramming glycolysis in cancer cells.