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: 10373031
• 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/10373031
• 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; Clinical Trials; 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; 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; Therapy Clinical Trials; Toxic effect; Tumor Immunity; Tumor-associated macrophages; Tumor-infiltrating immune cells; Tyrosine Kinase Inhibitor; United States; Work; Xenograft Model; base; cancer cell; cancer therapy; cell killing; cell motility; clinical application; clinical efficacy; design; effective therapy; in vivo; inhibitor; lung cancer cell; macrophage; 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是受体酪氨酸激酶的TAM（TYRO3、AXL、MERTK）家族的成员， 在癌细胞中异常表达，在那里它们起到促进细胞存活的作用。MERTK和AXL均介导 对多种细胞毒性化疗和分子靶向药物的耐药性，并在 巨噬细胞、自然杀伤细胞和其他先天性免疫细胞，它们在其中起抑制抗肿瘤的作用 免疫，导致增强的肿瘤生长和转移。这些数据和其他数据表明MERTK和AXL 作为多种人类肿瘤的治疗靶点。此外，由于MERTK的致癌作用， 和AXL在肿瘤和免疫细胞中的作用，预期抑制剂提供由两者介导的抗肿瘤作用。 直接杀死肿瘤细胞和调节先天免疫应答。许多小分子抑制剂和 靶向AXL或MERTK的抗体正在开发中，包括几种酪氨酸激酶抑制剂（TKI）， 目前正在进行临床试验。 尽管初始反应稳健，但靶向单一致癌驱动因子的TKI的临床疗效在历史上 由于获得性突变或代偿性旁路激活而产生耐药性， 信号具有共同下游信号通路的密切相关的蛋白质通常可以提供旁路 信号传导并从而介导抗性。事实上，MERTK介导对AXL抑制剂的耐药性，反之亦然， 这表明至少在某些情况下，MERTK和AXL的双重抑制可能是更有效的治疗方法， 与MERTK或AXL单独抑制相比，与该假设一致，MERTK和AXL抑制剂 在多种上皮癌中介导协同抗肿瘤活性。因此，MERTK的重叠角色 和AXL在肿瘤和免疫细胞中的作用，它们在抵抗各种疗法中的作用，以及它们在治疗中的双重作用。 肿瘤细胞和先天免疫系统支持靶向MERTK和AXL的药剂的开发。到 截至目前，INCB 081776是唯一描述的双重MERTK/AXL TKI;然而， 化合物尚未公开披露。 我们之前已经开发并优化了MERTK选择性TKI。我们假设在某些情况下， MERTK和AXL抑制剂将比靶向药物更有效地治疗NSCLC和其他癌症 MERTK或AXL单独给药。在这里，我们建议利用一种新的计算方法， 酶促、基于细胞的和药效学试验，以开发新型、强效和选择性双重MERTK， AXL抑制剂，并验证其在MERTK和AXL依赖性 皮下和原位NSCLC异种移植模型和免疫活性同基因NSCLC模型。在 这项工作完成后，我们预计将提供一个双重MERTK/AXL选择性抑制剂，适用于发展 多个种属的GLP毒性研究，支持IND申请的所有临床前验证研究 描述了该化合物，以及大规模合成该化合物的可行方法。