Drug design, development and therapy · 2024
Novel Dichloroacetophenone-Based PDHK1 Inhibitors as Potent Anticancer Agents.
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Wu Puhua, Zhang Zhicheng, Zhou Yan, Liu Quan, Tam Kin-Yip, Su Zhenhong
Аннотация
BACKGROUND: Pyruvate dehydrogenase kinases (PDHKs), important metabolic and abnormally expressed enzymes in cancer cells, are promising targets for cancer therapy, especially for non-small-cell lung cancer (NSCLC).
METHODS: In this study, a new hit, dichloroacetophenone (DAP) analog 9, was postulated to bind to the PDHK1 allosteric pocket, guided by molecular modeling and kinase biochemical experiments. Based on this binding mode, novel DAP analogs were designed and synthesized to confirm the importance of Phe180, Tyr411, and the hydrophobic core at the bottom of the pocket.
RESULTS: This structure-activity relationship (SAR) study led to the discovery of a novel potent hybrid scaffold, dichloroacetophenone biphenylsulfone ether. Dichloroacetophenone biphenylsulfone ether 31 and 32 inhibited PDHK1 with IC50 values of 86 and 140 nM, respectively.
CONCLUSION: Compound 32 with acceptable in vitro metabolic stability, predicted drug-likeness properties and ADME/T profiles, showed promising therapeutic efficacy in a lung cancer xenograft mouse model.
METHODS: In this study, a new hit, dichloroacetophenone (DAP) analog 9, was postulated to bind to the PDHK1 allosteric pocket, guided by molecular modeling and kinase biochemical experiments. Based on this binding mode, novel DAP analogs were designed and synthesized to confirm the importance of Phe180, Tyr411, and the hydrophobic core at the bottom of the pocket.
RESULTS: This structure-activity relationship (SAR) study led to the discovery of a novel potent hybrid scaffold, dichloroacetophenone biphenylsulfone ether. Dichloroacetophenone biphenylsulfone ether 31 and 32 inhibited PDHK1 with IC50 values of 86 and 140 nM, respectively.
CONCLUSION: Compound 32 with acceptable in vitro metabolic stability, predicted drug-likeness properties and ADME/T profiles, showed promising therapeutic efficacy in a lung cancer xenograft mouse model.
Предметные рубрики MeSH
HumansAnimalsAntineoplastic AgentsStructure-Activity RelationshipMiceAcetophenonesDrug Screening Assays, AntitumorPyruvate Dehydrogenase Acetyl-Transferring KinaseDose-Response Relationship, DrugMolecular StructureCell ProliferationProtein Kinase InhibitorsLung NeoplasmsProtein Serine-Threonine KinasesMice, NudeModels, MolecularCarcinoma, Non-Small-Cell LungNeoplasms, ExperimentalCell Line, TumorMice, Inbred BALB C