Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, School of Medicine, Hubei Polytechnic University, Huangshi, People's Republic of China.
Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China.
Drug Des Devel Ther. 2024 Oct 18;18:4661-4679. doi: 10.2147/DDDT.S473437. eCollection 2024.
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).
In this study, a new hit, dichloroacetophenone (DAP) analog , 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.
This structure-activity relationship (SAR) study led to the discovery of a novel potent hybrid scaffold, dichloroacetophenone biphenylsulfone ether. Dichloroacetophenone biphenylsulfone ether and inhibited PDHK1 with IC values of 86 and 140 nM, respectively.
Compound with acceptable metabolic stability, predicted drug-likeness properties and ADME/T profiles, showed promising therapeutic efficacy in a lung cancer xenograft mouse model.
丙酮酸脱氢酶激酶（PDHKs）是癌细胞中重要的代谢酶和异常表达的酶，是癌症治疗的有前途的靶点，特别是对非小细胞肺癌（NSCLC）。
在这项研究中，一种新的命中化合物二氯乙酮（DAP）类似物，通过分子建模和激酶生化实验，被假定与 PDHK1 变构口袋结合。基于这种结合模式，设计并合成了新型 DAP 类似物，以确认 Phe180、Tyr411 和口袋底部疏水区的重要性。
这项构效关系（SAR）研究发现了一种新型有效的混合支架，二氯乙酮联苯砜醚。二氯乙酮联苯砜醚和抑制 PDHK1 的 IC 值分别为 86 和 140 nM。
化合物具有可接受的代谢稳定性、预测的药物样性质和 ADME/T 特征，在肺癌异种移植小鼠模型中显示出有希望的治疗效果。
