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

一种新型高尔基体靶向抗癌药的作用机制 项目总结 为了治愈癌症，我们需要新的、可操作的治疗靶点，这些靶点与目前的治疗方法是相互垂直的。 实现新的联合治疗方案的战略。高尔基体GOLPH3途径已经成为一种 吸引人的目标。编码GOLPH3途径蛋白的基因(GOLPH3、MYO18A、PITPNC1和PI4KB) 都被发现在常见的人类癌症中经常被扩增和过度表达，作用于 导致癌症(包括肺癌、乳腺癌、结直肠癌和前列腺癌)。此外，该系统的功能 在已知的促癌基因中，GOLPH3途径是独一无二的，因为GOLPH3途径在 囊泡从高尔基体出来，运输到质膜上。GOLPH3的遗传干扰 途径(包括PI4P、GOLPH3、MYO18A或PI4KIII？)杀死培养和培养中的癌细胞 活体，而相对较少的正常细胞。因此，GOLPH3途径是一个有吸引力的新靶点 治疗学。我们已经利用高含量的GOLPH3途径鉴定出一种小分子抑制剂， 基于图像的、表现型、高通量屏幕。该化合物作用于MYO18A以损害高尔基体GOLPH3 途径功能，并优先杀死癌细胞。在这里，我们建议进行实验来确定 这种小分子的作用机制是通过识别直接的、机械的靶标。因此，我们将提供 GOLPH3途径致癌转化机制的新认识 GOLPH3途径，并支持进一步的药物化学，以实现从点击到领先的优化，目标是 开发一流的治疗剂。

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.