MERTK/AXL dual inhibitors provide novel treatment for cancer by targeting tumor cells and activating anti-tumor immunity

MERTK/AXL双重抑制剂通过靶向肿瘤细胞并激活抗肿瘤免疫为癌症提供新的治疗方法

• 批准号: 10589107
• 负责人: DOUGLAS K GRAHAM
• 金额: $ 49.71万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589107
• 关键词: ABCG2 gene; Adult; Advanced Malignant Neoplasm; Antibodies; Biochemical; Biological Assay; Bypass; Cancer Model; Cancer cell line; Carcinoma; Cell Survival; Cell physiology; Cells; Cellular Assay; Chemoresistance; Chemotherapy and/or radiation; Clinical Trials; Co-Immunoprecipitations; Combined Modality Therapy; Computing Methodologies; Cytotoxic Chemotherapy; Data; Development; Diagnosis; Disease; Distant Metastasis; Early treatment; Environment; Event; Family; Family member; Human; Immune; Immunocompetent; In Vitro; Innate Immune Response; Innate Immune System; Lead; MERTK gene; Macrophage; Malignant Neoplasms; Mediating; Methods; Molecular Target; Mus; Mutation; Natural Killer Cells; Neoplasm Metastasis; Newly Diagnosed; Non-Small-Cell Lung Carcinoma; Oncogenic; Operative Surgical Procedures; Outcome; Pain; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Phenotype; Phosphorylation; Phosphotransferases; Play; Prognosis; Property; Proteins; Quality of life; Receptor Protein-Tyrosine Kinases; Resistance; Resistance development; Role; Signal Pathway; Signal Transduction; Structure; Support System; Survival Rate; TYRO3 gene; Testing; Therapeutic; Toxic effect; Tumor Immunity; Tumor-associated macrophages; Tyrosine Kinase Inhibitor; United States; Work; Xenograft Model; cancer cell; cancer therapy; cell killing; cell motility; clinical application; clinical efficacy; design; effective therapy; in vivo; inhibitor; lung cancer cell; member; molecular dynamics; neoplastic cell; novel; pre-clinical; response; small molecule inhibitor; subcutaneous; targeted agent; targeted treatment; therapeutic target; therapeutically effective; tumor; tumor growth; tumorigenesis; validation studies

MERTK and AXL are members of the TAM (TYRO3, AXL, MERTK) family of receptor tyrosine kinases that are aberrantly expressed in cancer cells where they function to promote cell survival. Both MERTK and AXL mediate resistance to a variety of cytotoxic chemotherapies and molecularly-targeted agents and have additional roles in macrophages, natural killer cells, 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 MERTK and AXL as therapeutic targets in a wide variety of human tumors. Moreover, because of the oncogenic roles for MERTK and AXL 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. Numerous small molecule inhibitors and antibodies targeting AXL or MERTK are in development, including several tyrosine kinase inhibitors (TKIs) that are currently in clinical trials. Despite robust initial responses, clinical efficacy of TKIs that target a single oncogenic driver has historically been limited by development of resistance as a result of acquired mutations or activation of compensatory bypass signaling. Closely-related proteins that share common downstream signaling pathways can often provide bypass signaling and thereby mediate resistance. Indeed, MERTK mediates resistance to AXL inhibitors and vice versa, suggesting that at least in some cases, dual inhibition of MERTK and AXL may be a more effective therapeutic strategy than MERTK or AXL inhibition alone. Consistent with this hypothesis, MERTK and AXL inhibitors mediate synergistic anti-tumor activity in a variety of epithelial cancers. Thus, the overlapping roles for MERTK and AXL in tumor and immune cells, their roles in resistance to a variety of therapies, and their dual roles in tumor cells and the innate immune system support development of agents that target both MERTK and AXL. To date, INCB081776 is the only dual MERTK/AXL TKI described; however, the structure and selectivity of the compound have not been publicly disclosed. We have previously developed and optimized MERTK-selective TKIs. We hypothesize that in some cases a dual MERTK and AXL inhibitor will be more effective for treatment of NSCLC and other cancers than agents targeting MERTK or AXL alone. Here, we propose to utilize a novel computational methodology in combination with enzymatic, cell-based and pharmacodynamic assays to develop novel, potent, and selective dual MERTK and AXL inhibitors and validate their biochemical and functional activities in MERTK and AXL-dependent subcutaneous and orthotopic NSCLC xenograft models and immune-competent syngeneic NSCLC models. At the completion of this work, we expect to deliver a dual MERTK/AXL-selective inhibitor suitable for advancement to GLP toxicity studies in multiple species, all of the preclinical validation studies to support an IND application describing this compound, and a viable method for large-scale synthesis of the compound.

MERTK和AXL是TAM （TYRO3， AXL， MERTK）受体酪氨酸激酶家族的成员