新型二氯苯乙酮基 PDHK1 抑制剂作为强效抗癌剂。

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL

Drug Design, Development and Therapy Pub Date : 2024-10-18 eCollection Date: 2024-01-01 DOI:10.2147/DDDT.S473437

Puhua Wu, Zhicheng Zhang, Yan Zhou, Quan Liu, Kin-Yip Tam, Zhenhong Su

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引用次数: 0

摘要

背景：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，是有希望的癌症治疗靶点，尤其是非小细胞肺癌（NSCLC）：在这项研究中，通过分子建模和激酶生化实验，推测了一种新的靶点--二氯苯乙酮（DAP）类似物 9--与 PDHK1 异构口袋的结合。根据这种结合模式，设计并合成了新型 DAP 类似物，以证实 Phe180、Tyr411 和口袋底部疏水核心的重要性：这项结构-活性关系（SAR）研究发现了一种新型强效混合支架--二氯苯乙酮联苯砜醚。二氯苯乙酮联苯砜醚 31 和 32 可抑制 PDHK1，其 IC50 值分别为 86 和 140 nM：结论：化合物 32 具有可接受的体外代谢稳定性、预测的药物相似性和 ADME/T 特征，在肺癌异种移植小鼠模型中显示出良好的疗效。

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Novel Dichloroacetophenone-Based PDHK1 Inhibitors as Potent Anticancer Agents.

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.

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.