| Structural highlights
Function
PDK1_HUMAN Serine/threonine kinase that plays a key role in regulation of glucose and fatty acid metabolism and homeostasis via phosphorylation of the pyruvate dehydrogenase subunits PDHA1 and PDHA2. This inhibits pyruvate dehydrogenase activity, and thereby regulates metabolite flux through the tricarboxylic acid cycle, down-regulates aerobic respiration and inhibits the formation of acetyl-coenzyme A from pyruvate. Plays an important role in cellular responses to hypoxia and is important for cell proliferation under hypoxia. Protects cells against apoptosis in response to hypoxia and oxidative stress.[1] [2] [3] [4]
Publication Abstract from PubMed
Multiple screening approaches were carried out to identify novel chemistry starting for Pyruvate Dehydrogenase Kinases (PDHKs) inhibitors. Through hit triaging efforts and structure-based optimization, two series of ATP competitive inhibitors with single digit nanomolar enzymatic potency for PDHK1/2 and around 10-100-fold selectivity over PDHK4/3 were discovered. Approach of covalent inhibitor was explored to successfully improve the cellular target engagement to single digit micromolar range.
Discovery of ATP competitive PDHK1/2 dual inhibitors.,Xu H, Ding D, Han X, Miao K, Liang C, Yun H, Zhu W, Dey F, Zhao D, Wu Y, Reutlinger M, Yang J, Zhai G, Lin Z, Li C, Wu W, Xu B, Han L, Chen S, Huang X, Casagrande F, Hilbert M, Strebel Q, Wichert M, Westwood P, Schafer R, Roth D, Heer D, Tian X, Ma T, Zhang T, Zhao J, Urich E, Xia G, Lassen K, Shen HC, Zou G Bioorg Med Chem Lett. 2025 Mar 17;122:130190. doi: 10.1016/j.bmcl.2025.130190. PMID:40107630[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Gudi R, Bowker-Kinley MM, Kedishvili NY, Zhao Y, Popov KM. Diversity of the pyruvate dehydrogenase kinase gene family in humans. J Biol Chem. 1995 Dec 1;270(48):28989-94. PMID:7499431
- ↑ McFate T, Mohyeldin A, Lu H, Thakar J, Henriques J, Halim ND, Wu H, Schell MJ, Tsang TM, Teahan O, Zhou S, Califano JA, Jeoung NH, Harris RA, Verma A. Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells. J Biol Chem. 2008 Aug 15;283(33):22700-8. doi: 10.1074/jbc.M801765200. Epub 2008 , Jun 9. PMID:18541534 doi:http://dx.doi.org/10.1074/jbc.M801765200
- ↑ Hitosugi T, Fan J, Chung TW, Lythgoe K, Wang X, Xie J, Ge Q, Gu TL, Polakiewicz RD, Roesel JL, Chen GZ, Boggon TJ, Lonial S, Fu H, Khuri FR, Kang S, Chen J. Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism. Mol Cell. 2011 Dec 23;44(6):864-77. doi: 10.1016/j.molcel.2011.10.015. PMID:22195962 doi:http://dx.doi.org/10.1016/j.molcel.2011.10.015
- ↑ Kato M, Li J, Chuang JL, Chuang DT. Distinct structural mechanisms for inhibition of pyruvate dehydrogenase kinase isoforms by AZD7545, dichloroacetate, and radicicol. Structure. 2007 Aug;15(8):992-1004. Epub 2007 Aug 2. PMID:17683942 doi:10.1016/j.str.2007.07.001
- ↑ Xu H, Ding D, Han X, Miao K, Liang C, Yun H, Zhu W, Dey F, Zhao D, Wu Y, Reutlinger M, Yang J, Zhai G, Lin Z, Li C, Wu W, Xu B, Han L, Chen S, Huang X, Casagrande F, Hilbert M, Strebel Q, Wichert M, Westwood P, Schäfer R, Roth D, Heer D, Tian X, Ma T, Zhang T, Zhao J, Urich E, Xia G, Lassen K, Shen HC, Zou G. Discovery of ATP competitive PDHK1/2 dual inhibitors. Bioorg Med Chem Lett. 2025 Mar 17;122:130190. PMID:40107630 doi:10.1016/j.bmcl.2025.130190
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