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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：
10381542
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/10381542
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 Protac 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 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

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TAM （TYRO3， AXL， MERTK）受体酪氨酸激酶家族的一员。所有三个