Validating and Characterizing a New Melanoma Therapeutic Target

项目概要 激酶是癌症治疗的有价值的治疗靶点，近年来许多小 分子激酶抑制剂已被开发出来并取得了一些临床成功。一个新概念 其中靶向必需的但非突变的激酶与小分子相结合 驱动激酶抑制剂，最近批准的组合就是一个例子 BRAF 和 MEK 抑制剂治疗转移性黑色素瘤。我们最近的研究重点是 确定癌细胞如何获得肿瘤扩张所需的侵袭行为以及 转移，主要通过研究侵袭伪足，即富含肌动蛋白的质膜突起， 协调细胞外蛋白水解。我们使用高通量筛选来确定哪些 激酶调节黑色素瘤细胞中的侵袭伪足。我们屏幕上的热门游戏 TAO3 已受控 侵袭伪足的形成和功能、3维基质中的生长以及肿瘤外渗 和体内生长。我们已经鉴定出TAO3的小分子抑制剂，并解决了晶体 其催化域的结构，揭示了可以促进 选择性TAO3抑制剂的开发。 TAO3 是黑色素瘤的一个有前途的治疗靶点， 我们假设 TAO3 的小分子抑制剂会抑制肿瘤生长 入侵。这项研究是由癌症生物学专家的合作活动促成的， 生物化学和结构生物学，以及药物化学。它旨在增强我们的 了解一种正在研究的激酶，该激酶似乎在黑色素瘤中发挥重要作用 成长。此外，这些研究有可能促进新的开发 单独或联合治疗黑色素瘤和其他癌症 已经批准的代理商

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