Validating and Characterizing a New Melanoma Therapeutic Target

项目摘要 激酶是癌症治疗的有价值的治疗靶点，近年来许多小的 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。一种新概念 其中以基本但非突变的激酶与小分子结合为靶点 驱动蛋白激酶的抑制剂，最近批准了一种 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侵袭行为，这是肿瘤扩张和 转移，主要是通过研究隐足动物，富含肌动蛋白的质膜突起 协调细胞外蛋白质的降解。我们使用了高通量筛查来确定 蛋白激酶调节黑色素瘤细胞的内陷。我们屏幕上的最热门歌曲，TA03，控制 内翻足的形成和功能、在三维基质中的生长和肿瘤渗出 并在体内生长。我们已经确定了TAO_3的小分子缓蚀剂，并解决了晶体 其催化结构域的结构，揭示了独特的特征，可以促进 选择性TAO_3抑制剂的研究进展。TAO_3是治疗黑色素瘤的一个有前途的靶点， 我们假设TAO_3的小分子抑制剂会抑制肿瘤生长和 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 对似乎在黑色素瘤中起重要作用的未被研究的激酶的理解 成长。此外，这些研究有可能促进一种新的 治疗黑色素瘤或其他癌症，无论是单独治疗还是联合治疗 已批准的代理

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