Novel TYRO3 inhibitors for treatment of cancer

Tyro3是(Tyro3，Ax1，MERTK)受体酪氨酸激酶家族的成员。三个都是 家族成员在癌细胞中异常表达，在那里他们的功能是促进细胞存活，调节 对多种细胞毒性化疗药物和分子靶向药物的耐药性，并在 巨噬细胞和其他天然免疫细胞发挥抑制抗肿瘤免疫的功能，导致 促进肿瘤生长和转移。这些数据和其他数据表明，的蛋白激酶是潜在的 多种人类肿瘤的治疗靶点。此外，由于激酶的致癌作用 在肿瘤和免疫细胞中，抑制剂都有望通过直接介导的方式提供抗肿瘤作用。 肿瘤细胞杀伤和调节先天免疫反应。而的蛋白有重叠 功能，但在某些情况下，它们也发挥独特的作用。具体来说，我们的初步数据表明， 抗肿瘤免疫的抑制尤其依赖于Tyro3。 在这里，我们建议利用一支成熟而富有成效的研究团队，以及 计算机辅助药物设计以及酶、细胞和药效学分析，以开发新的， 高效、选择性的Tyro3抑制剂，并验证它们在Tyro3-中的生化和功能活性 依赖肿瘤异种移植模型和免疫活性同基因肿瘤模型。Tyro3可以本地化到 核及核定位抑制诱导结肠癌细胞凋亡，提示非 典型的致癌功能的Tyro3，这可能不是有效的靶向单独的激酶抑制。 因此，传统的小分子激酶抑制剂和蛋白水解靶向嵌合体(PROTAC)降解剂 将开发和比较选择性靶向泛素化和降解的Tyro3。在 完成这项工作后，我们预计将提供一种适用于GLP毒性的Tyro3选择性抑制剂 多个物种的研究，充分的临床前验证研究，以支持IND应用程序描述这一点 化合物，以及大规模合成该化合物的可行方法。

TYRO3 is a member of the TAM (TYRO3, AXL, MERTK) family of receptor tyrosine kinases. All three family members are aberrantly expressed in cancer cells, where they function to promote cell survival, mediate resistance to a variety of cytotoxic chemotherapies and molecularly-targeted agents and have additional roles in macrophages and other innate immune cells where they function to suppress anti-tumor immunity, leading to enhanced tumor growth and metastasis. These and other data implicate the TAM kinases as potential therapeutic targets in a wide variety of human tumors. Moreover, because of the oncogenic roles for TAM kinases in both tumor and immune cells, inhibitors are expected to provide anti-tumor action mediated by both direct tumor cell killing and modulation of the innate immune response. While the TAM kinases have overlapping functions, they also play unique roles in some contexts. Specifically, our preliminary data suggest that suppression of anti-tumor immunity is particularly dependent on TYRO3. Here, we propose to utilize a well-established and productive team of researchers along with computational-aided drug design and enzymatic, cell-based and pharmacodynamic assays to develop novel, potent, and selective TYRO3 inhibitors and validate their biochemical and functional activities in TYRO3- dependent tumor xenograft models and immune-competent syngeneic cancer models. TYRO3 can localize to the nucleus and inhibition of nuclear localization induced apoptosis in colon cancer cells, suggesting non- canonical oncogenic functions for TYRO3 which might not be effectively targeted by kinase inhibition alone. Thus, both traditional small molecule kinase inhibitors and proteolysis-targeting chimeric (PROTAC) degraders that selectively target TYRO3 for ubiquitination and degradation will be developed and compared. At the completion of this work, we expect to deliver a TYRO3-selective inhibitor suitable for advancement to GLP toxicity studies in multiple species, sufficient preclinical validation studies to support an IND application describing this compound, and a viable method for large-scale synthesis of the compound.