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。

基本信息

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
项目类别：
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

项目摘要

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依赖靶向癌症疗法的方法特异性细胞色素P450（CYP）酶选择性激活促毒物。与正常细胞相比许多癌症表达了更高水平的CYP酶，该酶代谢异生物学。我们试图利用 CYP酶的高表达在肿瘤内部局部转化为细胞毒素代谢激活。在“初步结果”部分中，我们描述了靶向肿瘤的抑制剂去饱和酶（SCD）。这酶会催化不饱和脂肪酸的引入。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。它们存在于营养贫困人口中环境并需要从头合成不饱和脂肪酸以合成膜，维持膜流动性，并从饱和脂肪酸和游离胆固醇的毒性作用中缓冲细胞。实际上，我们的SCD抑制剂对培养的人类癌细胞的NM毒性较低。尽管肝脏中SCD的抑制作用是无毒的，而肿瘤中SCD的抑制会阻碍其生长，但 SCD在皮肤中的抑制会导致毒性，这给了临床发展的障碍常规的SCD抑制剂。具体而言，用已知抑制剂治疗的小鼠患有皮脂细胞的萎缩。这些皮肤细胞需要SCD合成皮脂，其中含有脂肪酸和脂肪醇的酯。皮脂是通过毛囊排出皮肤上，以减少热量流失，并在眼睛和眼睑上进行润滑。作为皮脂细胞萎缩的结果是，用SCD抑制剂治疗的小鼠患有干眼，皮肤干燥和体温过低。总而言之，SCD活性对于肿瘤生长至关重要，肝脏中可分配，但在皮肤中也需要。因此，理想的抗癌治疗将抑制肿瘤中的SCD，但不会抑制皮肤细胞。我们在这里证明发现这种肿瘤靶向的剂。我们表明他们以亲药的形式惰性，但是SCD的NM抑制剂较低。此外，我们表明它们在肿瘤中被激活，但不在皮肤中。最初的体内实验表明肿瘤生长抑制和改善的治疗索引相对于SCD的非靶向抑制剂。我们描述了表征抑制剂互动的计划使用SCD，将它们优化为体内实用程序，并充分评估其作为抗癌剂的治疗潜力肺癌和肝癌的啮齿动物模型。拟议的研究应确定适用于晚期预先预先预先预先预先的靶向的靶向抑制剂临床发展，包括毒理学，配方和制造（未提出）。如果成功，我们将确定一种利用代谢的靶向癌症疗法的方法癌细胞的弱点。虽然在这里没有提出建议，但我们认识到可以调整此策略以利用其他过表达的CYP同工型和/或其他类别的细胞毒素。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Biomarkers for RBM39 degradation in acute myeloid leukemia.

DOI：
10.1038/s41375-020-0729-9
发表时间：
2020-07
期刊：
Leukemia
影响因子：
11.4
作者：
Hsiehchen D;Goralski M;Kim J;Xie Y;Nijhawan D
通讯作者：
Nijhawan D

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