Puhua Wu,1,2 Zhicheng Zhang,1 Yan Zhou,2 Quan Liu,2 Kin-Yip Tam,2 Zhenhong Su1 

1Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, School of Medicine, Hubei Polytechnic University, Huangshi, People’s Republic of China; 2Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, People’s Republic of China

Correspondence: Puhua Wu, Email wph75000@hotmail.com

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.

Keywords: PDHK1, dichloroacetophenone, allosteric pocket, anti-NSCLC activity, tumor xenograft mouse model