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Mechanism of Action of a Novel Golgi-Targeted Anti-Cancer Agent

新型高尔基体靶向抗癌剂的作用机制

基本信息

批准号：
10407638
负责人：
SETH J FIELD
金额：
$ 65.57万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10407638
关键词：
Affect Animal Model Antineoplastic Agents Biological Assay Biological Models Breast Cancerous Cell Culture Techniques Cell membrane Cells Colorectal Colorectal Cancer Complex Data F-Actin GOLPH3 gene Genes Genetic Goals Golgi Apparatus Golgi Targeting Human Image Impairment Lung Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Morphology Neoplasm Metastasis Normal Cell Oncogenes Oncogenic PIK4CB gene Pathway interactions Pharmaceutical Chemistry Phenotype Predisposition Prostate Proteins Publishing Regulation Series Set protein Shapes Signal Transduction Solid Neoplasm The Cancer Genome Atlas Therapeutic Therapeutic Agents Treatment Protocols United States National Institutes of Health Vesicle addiction base cancer cell cancer genomics cancer therapy cell transformation combinatorial effective therapy experimental study high throughput screening in vivo inhibitor insight lead optimization malignant breast neoplasm new therapeutic target novel overexpression programs receptor side effect small molecule small molecule inhibitor small molecule libraries success targeted treatment trafficking treatment strategy tumor progression

项目摘要

Mechanism of Action of a Novel Golgi-Targeted Anti-Cancer Agent PROJECT SUMMARY To cure cancer we need new, actionable targets for therapeutics that are orthogonal to current treatment strategies to enable new, combinatorial treatment regimens. The Golgi GOLPH3 pathway has emerged as an attractive target. Genes encoding GOLPH3 pathway proteins (GOLPH3, MYO18A, PITPNC1, and PI4KB) have all been identified as frequently amplified and over-expressed in common human cancers, acting to drive cancer (including lung, breast, colorectal, and prostate cancers). Furthermore, the function of the GOLPH3 pathway is unique among known cancer promoting genes in that the GOLPH3 pathway functions in vesicle exit from the Golgi for trafficking to the plasma membrane. Genetic interference with the GOLPH3 pathway (including depletion of PI4P, GOLPH3, MYO18A, or PI4KIII?) kills cancerous cells in culture and in vivo, while relatively sparing normal cells. Therefore, the GOLPH3 pathway is an attractive target for novel therapeutics. We have identified a small molecule inhibitor of the GOLPH3 pathway using a high-content, image-based, phenotypic, high-throughput screen. This compound acts on MYO18A to impair Golgi GOLPH3 pathway function and to preferentially kill cancerous cells. Here, we propose experiments to determine the mechanism of action of this small molecule by identifying the direct, mechanistic target. Thus, we will provide new insight into mechanisms of oncogenic transformation by the GOLPH3 pathway, regulation of the GOLPH3 pathway, and enable further medicinal chemistry for hit-to-lead optimization with the goal of developing a first in class therapeutic agent.

新型高尔基体靶向抗癌药物的作用机制项目摘要为了治愈癌症，我们需要新的，可操作的治疗靶点，这些靶点与当前的治疗方法正交战略，使新的，组合治疗方案。高尔基体GOLPH3通路已经成为一种有吸引力的目标。编码GOLPH3途径蛋白（GOLPH3、MYO18A、PITPNC1和PI4KB）的基因都被鉴定为在常见的人类癌症中频繁扩增和过度表达，癌症（包括肺癌、乳腺癌、结肠直肠癌和前列腺癌）。此外， GOLPH3途径在已知的癌症促进基因中是独特的，因为GOLPH3途径在癌症促进基因中起作用。囊泡从高尔基体出来运输到质膜。GOLPH3的遗传干扰途径（包括PI4P、GOLPH3、MYO18A或PI4KIII？消耗）杀死培养中的癌细胞，体内，而相对保留正常细胞。因此，GOLPH3途径是一个有吸引力的新靶点，治疗学我们已经鉴定了GOLPH 3途径的小分子抑制剂，基于图像、表型、高通量筛选。该化合物作用于MYO 18A以损害高尔基体GOLPH 3 通路的功能，并优先杀死癌细胞。在这里，我们提出实验来确定通过识别直接的、机械的靶标来研究这种小分子的作用机制。因此，我们将提供通过GOLPH3途径对致癌转化机制的新见解， GOLPH3途径，并使进一步的药物化学为目标的命中铅优化，开发出了第一种治疗药物