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：
10631058
负责人：
SETH J FIELD
金额：
$ 60.88万
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/10631058
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 Gene Expression 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 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.

新型高尔基抗癌剂的作用机理项目摘要为了治愈癌症，我们需要与当前治疗正交的治疗剂的新的，可操作的靶标实现新的组合治疗方案的策略。 Golgi Golph3途径已成为有吸引力的目标。编码Golph3途径蛋白的基因（Golph3，Myo18a，PitPNC1和PI4KB）所有人都被确定为常见的人类癌症，并过表达驱动癌症（包括肺，乳房，结直肠癌和前列腺癌）。此外， Golph3途径在已知的癌症促进基因中是独一无二的，因为Golph3途径在囊泡从高尔基体退出，用于运输到质膜。遗传干扰Golph3 途径（包括PI4P，Golph3，Myo18a或PI4KIII的耗竭）杀死培养物和在培养物中的癌细胞体内，同时相对保留正常细胞。因此，Golph3途径是新颖的目标疗法。我们已经使用高质体的，基于图像的表型，高通量屏幕。该化合物在Myo18a上作用，以损害Golgi Golph3 途径功能并优先杀死癌细胞。在这里，我们提出了实验以确定通过识别直接的机械靶标的该小分子的作用机理。因此，我们将提供对Golph3途径的致癌机制的新洞察力，调节 Golph3途径，并启用进一步的药物化学以进行命中至铅的优化，目的是开发课堂治疗剂的第一。