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Published on: February 9, 2021
Novel Dichloroacetophenone-Based PDHK1 Inhibitors as Potent Anticancer Agents
Puhua Wu1,2, Zhicheng Zhang1, Yan Zhou2
1Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, School of Medicine, Hubei Polytechnic University, Huangshi, People's Republic of China.
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.
Insights
Researchers developed novel dichloroacetophenone (DAP) analogs targeting pyruvate dehydrogenase kinases (PDHKs) for non-small-cell lung cancer (NSCLC) therapy. Compound 32 demonstrated promising efficacy in lung cancer models with good drug-like properties.
Area of Science:
- Medicinal Chemistry
- Biochemistry
- Oncology
Background:
- Pyruvate dehydrogenase kinases (PDHKs) are crucial metabolic enzymes and therapeutic targets in cancer, particularly non-small-cell lung cancer (NSCLC).
- Abnormal PDHK expression is linked to cancer cell metabolism, making them promising targets for novel anti-cancer drugs.
Purpose of the Study:
- To design and synthesize novel dichloroacetophenone (DAP) analogs targeting PDHK1.
- To investigate the structure-activity relationships (SAR) of these analogs for potent PDHK1 inhibition.
- To evaluate the therapeutic potential of lead compounds in preclinical lung cancer models.
Main Methods:
- Molecular modeling was used to postulate the binding mode of a DAP analog (compound 9) to the PDHK1 allosteric pocket.
- Novel DAP analogs were designed and synthesized based on the identified binding interactions.
- Biochemical kinase assays were performed to determine inhibitory activity (IC50 values).
- In vitro metabolic stability and ADME/T profiles were assessed.
- In vivo efficacy was evaluated in a lung cancer xenograft mouse model.
Main Results:
- A novel hybrid scaffold, dichloroacetophenone biphenylsulfone ether, was discovered through SAR studies.
- Compounds 31 and 32 potently inhibited PDHK1, with IC50 values of 86 nM and 140 nM, respectively.
- Compound 32 exhibited favorable in vitro metabolic stability and drug-likeness properties.
Conclusions:
- Novel DAP analogs targeting PDHK1 were successfully designed and synthesized.
- Compound 32 demonstrated significant therapeutic efficacy in a lung cancer xenograft model.
- The developed compounds represent promising candidates for further development as NSCLC therapeutics.
