Novel TYRO3 inhibitors for treatment of cancer

用于治疗癌症的新型 TYRO3 抑制剂

• 批准号: 10182743
• 负责人: DOUGLAS K GRAHAM
• 金额: $ 33.7万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10182743
• 关键词: Acute leukemia; Adult; Advanced Malignant Neoplasm; Apoptosis; Biochemical; Biological Assay; Cancer Model; Cell Line; Cell Nucleus; Cell Proliferation; Cell Survival; Cell physiology; Cells; Cellular Assay; Chemotherapy and/or radiation; Clinical Trials; Colon Carcinoma; Colorectal Cancer; Cytotoxic Chemotherapy; Data; Development; Diagnosis; Disease; Drug Design; Drug Kinetics; Family; Family member; Hematologic Neoplasms; Human; Immune; Immunocompetent; Immunooncology; Innate Immune Response; Large Intestine Carcinoma; Lead; Lymphoma; Lymphoma cell; MERTK gene; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Malignant neoplasm of urinary bladder; Mediating; Melanoma Cell; Methods; Modeling; Molecular Target; Mus; Neoplasm Metastasis; Nuclear; Oncogenic; Operative Surgical Procedures; Outcome; Pain; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Phosphorylation; Phosphotransferases; Play; Prognosis; Property; Proteolysis; Quality of life; Receptor Protein-Tyrosine Kinases; Research Personnel; Resistance; Role; Structure; TYRO3 gene; Therapeutic; Toxic effect; Tumor Immunity; Tumor-infiltrating immune cells; Tyrosine Kinase Inhibitor; Ubiquitination; United States; Work; Xenograft Model; base; cancer cell; cancer therapy; cell killing; clinical application; clinical translation; effective therapy; in vivo; inhibitor/antagonist; kinase inhibitor; macrophage; malignant breast neoplasm; melanoma; member; neoplastic cell; novel; pre-clinical; small molecule; subcutaneous; targeted agent; targeted treatment; therapeutic target; tumor; tumor growth; tumor xenograft; validation studies

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.

TYRO3 是受体酪氨酸激酶 TAM（TYRO3、AXL、MERTK）家族的成员。全部三个 家族成员在癌细胞中异常表达，它们的功能是促进细胞存活、介导 对多种细胞毒性化疗和分子靶向药物产生耐药性，并在以下方面发挥额外作用： 巨噬细胞和其他先天免疫细胞的功能是抑制抗肿瘤免疫，从而导致 增强肿瘤生长和转移。这些和其他数据表明 TAM 激酶具有潜力 多种人类肿瘤的治疗靶点。此外，由于 TAM 激酶的致癌作用 在肿瘤和免疫细胞中，抑制剂有望提供由直接介导的抗肿瘤作用 肿瘤细胞杀伤和先天免疫反应的调节。虽然 TAM 激酶有重叠 除了功能之外，它们在某些情况下也发挥着独特的作用。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，我们建议利用一支完善且富有成效的研究团队以及 计算辅助药物设计以及酶促、基于细胞和药效学测定，以开发新颖的、 强效、选择性 TYRO3 抑制剂，并验证其在 TYRO3- 中的生化和功能活性 依赖性肿瘤异种移植模型和免疫活性同基因癌症模型。 TYRO3 可以本地化到 细胞核和核定位的抑制诱导结肠癌细胞凋亡，表明非 TYRO3 的典型致癌功能可能无法仅通过激酶抑制来有效靶向。 因此，传统的小分子激酶抑制剂和蛋白水解靶向嵌合（PROTAC）降解剂 将开发和比较选择性靶向 TYRO3 进行泛素化和降解的方法。在 完成这项工作后，我们期望提供一种适用于 GLP 毒性进展的 TYRO3 选择性抑制剂 多个物种的研究，足够的临床前验证研究来支持描述这一点的 IND 申请 化合物，以及大规模合成该化合物的可行方法。