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Principal Investigator: DOUGLAS K GRAHAM
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2024
Award: $306,926
Funding agency: National Cancer Institute
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.
Terms: <21+ years old><Acute leukemia><Adult><Adult Human><Advanced Cancer><Advanced Malignant Neoplasm><Assay><Bioassay><Biochemical><Biological Assay><Bladder Cancer><Breast Cancer><Cancer Model><Cancer Treatment><CancerModel><Cancers><Cell Body><Cell Function><Cell Growth in Number><Cell Line><Cell Multiplication><Cell Nucleus><Cell Physiology><Cell Process><Cell Proliferation><Cell Survival><Cell Viability><CellLine><Cells><Cellular Assay><Cellular Function><Cellular Physiology><Cellular Process><Cellular Proliferation><Chemotherapy and Radiation><Chemotherapy and/or radiation><Clinical Trials><Colon Cancer><Colon Carcinoma><Colorectal Cancer><Colorectal Carcinomas><Cytotoxic Chemotherapy><Cytotoxic Therapy><Data><Development><Diagnosis><Disease><Disorder><Drug Design><Drug Kinetics><Drugs><Family><Family member><Germinoblastic Sarcoma><Germinoblastoma><Hematologic Cancer><Hematologic Malignancies><Hematologic Neoplasms><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematopoietic Cancer><Hepatic Cancer><Human><Immune><Immunes><Immunocompetent><Immunooncology><Induction of Apoptosis><Innate Immune Response><Investigators><Kinases><Large Bowel Carcinoma><Large Intestine Carcinoma><Lead><Lymphoma><Lymphoma cell><MER Tyrosine Kinase Protooncogene><MERTK><MERTK gene><Macrophage><Malignant Bladder Neoplasm><Malignant Breast Neoplasm><Malignant Cell><Malignant Hematologic Neoplasm><Malignant Lymphoma><Malignant Melanoma><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Ovarian Neoplasm><Malignant Ovarian Tumor><Malignant Tumor><Malignant Tumor of the Bladder><Malignant Tumor of the Lung><Malignant Tumor of the Ovary><Malignant Tumor of the Prostate><Malignant neoplasm of liver><Malignant neoplasm of lung><Malignant neoplasm of ovary><Malignant neoplasm of prostate><Malignant neoplasm of urinary bladder><Malignant prostatic tumor><Mediating><Medication><Medicinal Chemistry><Melanoma><Melanoma Cell><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Methods><Mice><Mice Mammals><Modeling><Modern Man><Molecular Target><Murine><Mus><Mφ><Neoplasm Metastasis><Nuclear><Nucleus><Oncogenic><Operative Procedures><Operative Surgical Procedures><Outcome><Ovary Cancer><PTK Inhibitors><PTK Receptors><Pain><Painful><Patients><Pb element><Pharmaceutic Chemistry><Pharmaceutical Chemistry><Pharmaceutical Preparations><Pharmacodynamics><Pharmacokinetics><Phosphorylation><Phosphotransferase Gene><Phosphotransferases><Play><Productivity><Prognosis><Property><Prostate CA><Prostate Cancer><Prostate malignancy><Prostatic Cancer><Protac><Protein Phosphorylation><Protein Tyrosine Kinase Inhibitors><Proteolysis targeting chimeric><Pulmonary Cancer><Pulmonary malignant Neoplasm><QOL><Quality of life><Receptor Protein-Tyrosine Kinases><Receptor Tyrosine Kinase Gene><Research Personnel><Researchers><Resistance><Reticulolymphosarcoma><Role><Secondary Neoplasm><Secondary Tumor><Strains Cell Lines><Structure><Subcellular Process><Surgical><Surgical Interventions><Surgical Procedure><TK Inhibitors><TYRO3><TYRO3 gene><Therapeutic><Toxic effect><Toxicities><Transmembrane Receptor Protein Tyrosine Kinase><Transphosphorylases><Tumor Cell><Tumor Immunity><Tumor Promotion><Tyrosine Kinase Inhibitor><Tyrosine Kinase Linked Receptors><Tyrosine Kinase Receptors><Ubiquitilation><Ubiquitination><Ubiquitinoylation><United States><Urinary Bladder Cancer><Urinary Bladder Malignant Tumor><Work><Xenograft Model><adulthood><anti-cancer therapy><anti-tumor immunity><antitumor immunity><cancer cell><cancer immunity><cancer in the colon><cancer metastasis><cancer therapy><cancer-directed therapy><cell assay><cell killing><chemo/radiation therapy><chemotherapy and radiotherapy><clinical applicability><clinical application><clinical translation><clinically translatable><cultured cell line><developmental><drug/agent><effective therapy><effective treatment><heavy metal Pb><heavy metal lead><immune competent><immune-oncology><immuno oncology><immunology oncology><in vivo><inhibitor><kinase inhibitor><liver cancer><liver malignancy><lung cancer><malignancy><malignant breast tumor><malignant liver tumor><member><neoplasm/cancer><neoplastic cell><novel><oncoimmunology><ovarian cancer><pre-clinical><preclinical><proteolysis targeting chimera><radiation or chemotherapy><resistant><small molecule><social role><subcutaneous><subdermal><surgery><targeted agent><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><tumor><tumor cell metastasis><tumor growth><tumor xenograft><ubiquination><ubiquitin conjugation><validation studies><xenograft transplant model><xenotransplant model>