Validating and Characterizing a New Melanoma Therapeutic Target

项目摘要 激酶是用于癌症治疗的有价值的治疗靶标，并且近年来许多小的激酶被用于癌症治疗。 分子激酶抑制剂已经被开发出来并在临床上取得了一些成功。一个新概念 其中靶向必需的但未突变的激酶与小分子 驱动激酶的抑制剂，已经通过最近批准的 BRAF和MEK抑制剂用于转移性黑色素瘤。我们最近的研究集中在 确定癌细胞如何获得肿瘤扩张所需的侵入行为， 转移，主要是通过研究侵入伪足，富含肌动蛋白的质膜突起， 协调胞外蛋白水解。我们使用高通量筛选来确定 激酶调节黑色素瘤细胞中的侵袭伪足。我们屏幕上的最高命中，TAO3， 侵袭性伪足的形成和功能、在三维基质中的生长和肿瘤外渗 和体内生长。我们已经确定了TAO3的小分子抑制剂，并解决了晶体 其催化结构域的结构，揭示了独特的功能，可以促进 开发选择性TAO3抑制剂。TAO3是黑色素瘤中有前途的治疗靶点， 我们假设TAO3的小分子抑制剂将抑制肿瘤生长， 入侵这项研究是由癌症生物学专家的合作活动， 生物化学和结构生物学以及药物化学。它旨在提高我们的 了解一种未充分研究的激酶，它似乎在黑色素瘤中起重要作用 增长此外，这些研究有可能促进新的 用于治疗黑色素瘤和可能的其他癌症，单独或与 已批准的代理商

Project Summary Kinases are valuable therapeutic targets for cancer treatment, and in recent years many small molecule kinase inhibitors have been developed and had some clinical success. A new concept in which targeting essential, but non-mutated, kinases in combination with small molecule inhibitors of driver kinases, has been exemplified by the recent approval of the combination of a BRAF and a MEK inhibitor for metastatic melanoma. Our recent research focuses on determining how cancer cells acquire invasive behavior, required for tumor expansion and metastasis, primarily by studying invadopodia, actin-rich plasma membrane protrusions that coordinate extracellular proteolysis. We used a high throughput screen to determine which kinases regulate invadopodia in melanoma cells. The top hit from our screen, TAO3, controlled invadopodia formation and function, growth in 3-dimensional matrices, and tumor extravasation and growth in vivo. We have identified small molecule inhibitors of TAO3, and solved the crystal structure of its catalytic domain, revealing unique features which could facilitate the development of selective TAO3 inhibitors. TAO3 is a promising therapeutic target in melanoma, and we hypothesize that small molecule inhibitors of TAO3 will inhibit tumor growth and invasion. This research is enabled by the collaborative activities of experts in cancer biology, biochemistry and structural biology, and medicinal chemistry. It is designed to enhance our understanding of an understudied kinase which appears to play an important role in melanoma growth. Furthermore, these studies have the potential to promote the development of a new therapeutic for melanoma and perhaps other cancers, either alone or in combination with already approved agents