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Crystal structure of human pyruvate dehydrogenase kinase isoform 1 in complex with ATP competitive inhibitor 8
Structural highlights
FunctionPDK1_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 PubMedMultiple 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
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