Tumor-targeted inhibitors of stearoyl-CoA desaturase for the treatment of cancer.

用于治疗癌症的肿瘤靶向硬脂酰辅酶A去饱和酶抑制剂。

• 批准号: 10358563
• 负责人: DEEPAK NIJHAWAN
• 金额: $ 44.2万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-07 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10358563
• 关键词: Affect; Antineoplastic Agents; Atrophic; Buffers; CYP4F11 gene; Cancer Model; Cancer cell line; Cancerous; Cell Line; Cells; Characteristics; Chemicals; Cholesterol; Consumption; Cytochrome P450; Cytotoxin; Data; Environment; Enzyme Inhibitor Drugs; Enzymes; Esters; Eye; Eyelid structure; Fatty Acids; Fatty Alcohols; Fatty acid glycerol esters; Formulation; Foxes; Genetically Engineered Mouse; Goals; Growth; Hair follicle structure; Heat Losses; Human; In Vitro; Liver; Lubrication; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of lung; Mass Spectrum Analysis; Mediating; Medical Oncologist; Membrane; Membrane Fluidity; Metabolic; Metabolic Activation; Metabolism; Mus; Normal Cell; Normal tissue morphology; Nutrient; Physicians; Prodrugs; Protein Isoforms; Rodent Model; Saturated Fatty Acids; Scientist; Sebum; Skin; Solubility; Stearoyl-CoA Desaturase; Testing; Therapeutic; Therapeutic Index; Toxic effect; Toxicology; Unsaturated Fatty Acids; X-Ray Crystallography; Xenobiotics; Xenograft Model; adduct; anticancer treatment; benzothiazole; cancer cell; cancer therapy; clinical development; comparative efficacy; cytotoxicity; drug discovery; experimental study; eye dryness; high throughput screening; human cancer mouse model; improved; in vivo; inhibitor; mouse model; natural hypothermia; neoplastic cell; overexpression; preclinical development; scaffold; small molecule; targeted agent; targeted cancer therapy; targeted treatment; tumor; tumor growth

The ideal treatments for cancer achieve a therapeutic index by exploiting the differences between cancerous and normal cells. Here we describe an approach to develop targeted cancer therapies that relies on selective activation of a pro-drug by specific cytochrome P450 (CYP) enzymes. Compared to normal cells, many cancers express higher levels of CYP enzymes, which metabolize xenobiotics. We seek to exploit the high expression of CYP enzymes to locally convert an inert molecule into a cytotoxin within the tumor through metabolic activation. In the Preliminary Results section we describe tumor-targeted inhibitors of stearoyl CoA desaturase (SCD). This enzyme catalyzes the introduction of unsaturation into fatty acids. Tumor cells require high levels of unsaturated fatty acids and are therefore sensitive to SCD inhibitors. They exist in a nutrient poor environment and require de novo synthesis of unsaturated fatty acids to synthesize membranes, maintain membrane fluidity, and buffer the cell from the toxic effects of saturated fatty acids and free cholesterol. Indeed, our SCD inhibitors display low nM toxicity towards cultured human cancer cells. While inhibition of SCD in the liver is non-toxic, and inhibition of SCD within tumors arrests their growth, inhibition of SCD in the skin results in toxicity that presents an obstacle to the clinical development of conventional SCD inhibitors. Specifically, mice treated with known inhibitors suffer atrophy of sebocytes. These skin cells require SCD to synthesize sebum, which contains esters of fatty acids and fatty alcohols. Sebum is excreted onto the skin by hair follicles to reduce heat loss and onto the eyes and eyelids for lubrication. As a result of sebocyte atrophy, mice treated with SCD inhibitors suffer from dry eye, dry skin and hypothermia. In summary, SCD activity is critical for tumor growth, dispensable in the liver, but also required in the skin. An ideal anti-cancer treatment would therefore inhibit SCD in the tumor but not skin cells. Here we demonstrate the discovery of such tumor-targeted agents. We show that they are inert in their pro-drug form, but low nM inhibitors of SCD in their active form. Furthermore, we show that they are activated in tumors, but not in skin. Initial in vivo experiments demonstrate both tumor growth inhibition and an improved therapeutic index relative to non-targeted inhibitors of SCD. We describe plans to characterize the inhibitors' interactions with SCD, optimize them for in vivo utility, and fully evaluate their therapeutic potential as anti-cancer agents in rodent models of lung and liver cancer. The proposed studies should identify an optimized, targeted inhibitor of SCD suitable for advanced pre- clinical development including IND-enabling toxicology, formulation and manufacturing (not proposed). If successful, we will have identified an approach to targeted cancer therapies that exploits a metabolic weakness of cancer cells. While not proposed here, we recognize that this strategy could be tuned to exploit other over-expressed CYP isoforms and/or other classes of cytotoxins.

癌症的理想治疗方法通过利用以下因素之间的差异来实现治疗指数： 癌细胞和正常细胞。在这里，我们描述了一种开发靶向癌症治疗的方法， 前体药物通过特定的细胞色素P450（CYP 1A 1）酶的选择性活化。与正常细胞相比， 许多癌症表达更高水平的代谢异生物质的β-淀粉酶。我们寻求利用 高表达的DNA酶，以在肿瘤内局部转化惰性分子为细胞毒素， 代谢活化在初步结果部分，我们描述了硬脂酰CoA的肿瘤靶向抑制剂 去饱和酶（SCD）。这种酶催化将不饱和引入脂肪酸。肿瘤细胞需要 高水平的不饱和脂肪酸，因此对SCD抑制剂敏感。它们生活在一个营养贫乏的 环境和需要从头合成的不饱和脂肪酸合成膜，维持 膜流动性，并缓冲饱和脂肪酸和游离胆固醇的毒性作用的细胞。 事实上，我们的SCD抑制剂对培养的人癌细胞显示出低nM毒性。 虽然肝脏中SCD的抑制是无毒的，并且肿瘤内SCD的抑制阻止了它们的生长， 皮肤中SCD的抑制导致毒性，这阻碍了 常规SCD抑制剂。具体地，用已知抑制剂处理的小鼠遭受皮脂细胞萎缩。这些 皮肤细胞需要SCD来合成含有脂肪酸和脂肪醇的酯的皮脂。皮脂是 通过毛囊分泌到皮肤上以减少热量损失，并分泌到眼睛和眼睑上以润滑。作为 由于皮脂腺细胞萎缩，用SCD抑制剂治疗的小鼠患有干眼、皮肤干燥和体温过低。 总之，SCD活性对于肿瘤生长至关重要，不仅在肝脏中是必需的，而且在皮肤中也是必需的。 因此，理想的抗癌治疗将抑制肿瘤中的SCD，而不是皮肤细胞。这里我们 证明了这种肿瘤靶向药物的发现。我们发现它们在前药形式下是惰性的， 但其活性形式的SCD的低nM抑制剂。此外，我们发现它们在肿瘤中被激活， 不是在皮肤上。最初的体内实验证明了肿瘤生长抑制和改善的治疗效果。 相对于SCD的非靶向抑制剂的指数。我们描述了表征抑制剂相互作用的计划 与SCD，优化它们的体内效用，并充分评估其作为抗癌药物的治疗潜力， 肺癌和肝癌的啮齿动物模型。 拟议的研究应确定一个优化的，有针对性的SCD抑制剂，适用于先进的前， 临床开发，包括IND启用毒理学、制剂和生产（未拟定）。如果 如果成功，我们将确定一种靶向癌症治疗的方法， 癌细胞的弱点虽然这里没有提出，但我们认识到可以调整此策略以利用 其它过表达的α-淀粉酶同工型和/或其它种类的细胞毒素。

项目成果

Discovery of Cytochrome P450 4F11 Activated Inhibitors of Stearoyl Coenzyme A Desaturase.

细胞色素 P450 4F11 激活的硬脂酰辅酶 A 去饱和酶抑制剂的发现。

• DOI: 10.1021/acs.jmedchem.8b00052
• 发表时间: 2018
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Winterton,SarahE;Capota,Emanuela;Wang,Xiaoyu;Chen,Hong;Mallipeddi,PremaL;Williams,NoelleS;Posner,BruceA;Nijhawan,Deepak;Ready,JosephM
• 通讯作者: Ready,JosephM