Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 8461-8479 |
| Number of pages | 19 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 62 |
| Issue number | 18 |
| DOIs | |
| Publication status | Published - 2019 Sep 26 |
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ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
Cite this
Identification of Novel Resorcinol Amide Derivatives as Potent and Specific Pyruvate Dehydrogenase Kinase (PDHK) Inhibitors. / Cho, Hanna; Shin, Injae; Cho, Kyungseon; Yoon, Hojong; Yoo, Eun Kyung; Kim, Mi Jin; Park, Sungmi; Lee, In Kyu; Kim, Nam Doo; Sim, Taebo.
In: Journal of Medicinal Chemistry, Vol. 62, No. 18, 26.09.2019, p. 8461-8479.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Identification of Novel Resorcinol Amide Derivatives as Potent and Specific Pyruvate Dehydrogenase Kinase (PDHK) Inhibitors
AU - Cho, Hanna
AU - Shin, Injae
AU - Cho, Kyungseon
AU - Yoon, Hojong
AU - Yoo, Eun Kyung
AU - Kim, Mi Jin
AU - Park, Sungmi
AU - Lee, In Kyu
AU - Kim, Nam Doo
AU - Sim, Taebo
PY - 2019/9/26
Y1 - 2019/9/26
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85072687328&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.9b00565
DO - 10.1021/acs.jmedchem.9b00565
M3 - Article
C2 - 31469962
AN - SCOPUS:85072687328
VL - 62
SP - 8461
EP - 8479
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 18
ER -