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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：
10247801
负责人：
SETH J FIELD
金额：
$ 73.31万
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/10247801
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/antagonist 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剂的作用机制项目概要为了治愈癌症，我们需要与当前治疗正交的新的、可行的治疗目标启用新的组合治疗方案的策略。高尔基体 GOLPH3 通路已成为有吸引力的目标。编码 GOLPH3 通路蛋白的基因（GOLPH3、MYO18A、PITPNC1 和 PI4KB）所有这些都已被确定在常见的人类癌症中经常被扩增和过度表达，从而发挥作用导致癌症（包括肺癌、乳腺癌、结直肠癌和前列腺癌）。此外，该功能的 GOLPH3 通路在已知的促癌基因中是独一无二的，因为 GOLPH3 通路在囊泡从高尔基体出口运输到质膜。 GOLPH3 的遗传干扰途径（包括 PI4P、GOLPH3、MYO18A 或 PI4KIII 的耗竭？）可杀死培养物和环境中的癌细胞体内，同时相对保留正常细胞。因此，GOLPH3 通路是一个有吸引力的新靶标。疗法。我们使用高含量、基于图像的表型高通量筛选。该化合物作用于 MYO18A，损害高尔基体 GOLPH3 通路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靶标来了解该小分子的作用机制。因此，我们将提供对 GOLPH3 途径致癌转化机制的新见解， GOLPH3 途径，并实现进一步的药物化学，以实现从命中到先导的优化，目标是开发一流的治疗剂。