Cho, Hanna Shin, Injae Cho, Kyungseon Yoon, Hojong Yoo, Eun Kyung Kim, Mi-Jin Park, Sungmi Lee, In-Kyu Kim, Nam Doo Sim, Taebo 2024-01-19T19:04:07Z 2024-01-19T19:04:07Z 2021-09-05 2019-09-26 0022-2623 https://pubs.kist.re.kr/handle/201004/119555 Pyruvate dehydrogenase kinases (PDHKs) promote abnormal respiration in cancer cells. Studies with novel resorcinol amide derivatives based on VER-246608 (6) led to the identification of 19n and 19t containing five-membered heteroaromatic rings as unique structural features. These substances possess single-digit nanomolar activities against PDHKs. 19t exhibits higher potencies against PDHK1/2/4 than does 6 and inhibits only PDHKs among 366 kinases. Moreover, 19g, 19l, and 19s were found to be isotype-selective PDHK inhibitors. Molecular dynamics simulations provide a better understanding of how the heteroaromatic rings affect the activities of 19n and 19t on PDHK1/2/3/4. Moreover, 19n possesses a much higher antiproliferative activity against cancer cells than does 6. We demonstrated that the results of PDH assays better correlate with cellular activities than do those of PDHK kinase assays. Furthermore, 19n induces apoptosis of cancer cells via mitochondrial dysfunction, suppresses tumorigenesis, and displays a synergistic effect on satraplatin suppression of cancer cell proliferation. English AMER CHEMICAL SOC BIOLOGICAL EVALUATION CANCER DICHLOROACETATE METABOLISM EXPRESSION AZD7545 BINDING PYRUVATE-DEHYDROGENASE-KINASE-2 PHOSPHORYLATION RESISTANCE Identification of Novel Resorcinol Amide Derivatives as Potent and Specific Pyruvate Dehydrogenase Kinase (PDHK) Inhibitors Article 10.1021/acs.jmedchem.9b00565 1 JOURNAL OF MEDICINAL CHEMISTRY, v.62, no.18, pp.8461 - 8479 JOURNAL OF MEDICINAL CHEMISTRY 62 18 8461 8479 scie scopus 000488334500006 2-s2.0-85072687328 Chemistry, Medicinal Pharmacology & Pharmacy Article BIOLOGICAL EVALUATION CANCER DICHLOROACETATE METABOLISM EXPRESSION AZD7545 BINDING PYRUVATE-DEHYDROGENASE-KINASE-2 PHOSPHORYLATION RESISTANCE