Novel TYRO3 inhibitors for treatment of cancer

用于治疗癌症的新型 TYRO3 抑制剂

基本信息

批准号：
10582629
负责人：
DOUGLAS K GRAHAM
金额：
$ 31.66万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
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/10582629
关键词：
Acute leukemia Adult Advanced Malignant Neoplasm 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 Induction of Apoptosis Innate Immune Response Large Intestine Carcinoma Lead Lymphoma Lymphoma cell MERTK gene Macrophage 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 Productivity Prognosis Property Protac Quality of life Receptor Protein-Tyrosine Kinases Research Personnel Resistance Role Structure TYRO3 gene Therapeutic Toxic effect Tumor Immunity Tumor Promotion Tyrosine Kinase Inhibitor Ubiquitination United States Work Xenograft Model cancer cell cancer therapy cell killing clinical application clinical translation effective therapy in vivo inhibitor kinase inhibitor 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

项目摘要

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是受体酪氨酸激酶的TAM（Tyro3，Axl，Mertk）家族的成员。这三个家庭成员在癌细胞中异常表达，在癌细胞中起作用以促进细胞存活，介导对多种细胞毒性化学疗法和分子靶向剂的抗性，并在巨噬细胞和其他先天免疫细胞在其起作用以抑制抗肿瘤免疫力，导致增强的肿瘤生长和转移。这些和其他数据将TAM激酶视为潜力各种各样的人类肿瘤中的治疗靶标。而且，由于TAM激酶的致癌作用在肿瘤和免疫细胞中，预计抑制剂将提供抗肿瘤作用。先天免疫反应的肿瘤细胞杀死和调节。而Tam激酶有重叠功能，它们在某些情况下还扮演着独特的角色。具体而言，我们的初步数据表明抗肿瘤免疫的抑制特别取决于Tyro3。在这里，我们建议利用一个良好且富有成效的研究人员团队计算辅助药物设计和酶促，基于细胞的和药效学测定，以开发新颖，有效和选择性Tyro3抑制剂，并在Tyro3-中验证其生化和功能活性依赖性肿瘤异种移植模型和免疫能力的合成癌模型。 tyro3可以本地化核定位的细胞核和抑制诱导结肠癌细胞凋亡，表明非 - TYRO3的规范致癌功能可能仅受激酶抑制可能有效地靶向。因此，传统的小分子激酶抑制剂和靶向蛋白水解嵌合（Protac）降解器将有选择地靶向Tyro3用于泛素化和降解。在完成这项工作，我们希望提供适合于GLP毒性提高的TYRO3选择性抑制剂在多种物种中的研究，足够的临床前验证研究以支持描述这一点的IND应用化合物，也是该化合物大规模合成的可行方法。