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，它们在促进细胞存活中起作用。 MERTK和AXL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，天然杀伤细胞和其他先天免疫细胞在其中起作用以抑制抗肿瘤 免疫力，导致肿瘤生长和转移增强。这些和其他数据暗示了Mertk和Axl 作为各种人类肿瘤的治疗靶标。而且，由于MERTK的致癌作用 在肿瘤和免疫细胞中的AXL和AXL，预计抑制剂将提供两者介导的抗肿瘤作用 直接的肿瘤细胞杀死和先天免疫反应的调节。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） 目前正在临床试验中。 尽管初始反应强大，但针对单个致癌驱动器的TKI的临床功效在历史上具有 由于获得的突变或代码旁路的激活而受到阻力发展的限制 信号。密切相关的蛋白质共享共同的下游信号通路通常可以提供旁路 信号传导，从而介导电阻。实际上，MERTK介导对AXL抑制剂的抗性，反之亦然， 提示至少在某些情况下，对MERTK和AXL的双重抑制可能是更有效的治疗方法 策略比仅MERTK或AXL抑制作用。与该假设一致，MERTK和AXL抑制剂 介导各种上皮癌中的协同抗肿瘤活性。因此，MERTK的重叠角色 在肿瘤和免疫细胞中的AXL，它们在对多种疗法的耐药性中的作用，并且它们在双重作用中 肿瘤细胞和先天免疫系统支持靶向MERTK和AXL的药物的开发。到 日期，INCB081776是唯一描述的双MERTK/AXL TKI；但是， 化合物尚未公开披露。 我们以前已经开发并优化了MERTK选择性TKI。我们假设在某些情况下是双重 MERTK和AXL抑制剂将比针对剂量的药物更有效地治疗NSCLC和其他癌症 单独使用MERTK或AXL。在这里，我们建议利用一种新颖的计算方法与 酶促，基于细胞和药效学测定，以开发新颖，有效和选择性双MERTK和 AXL抑制剂并验证其在MERTK和AXL依赖性中的生化和功能活性 皮下和原位NSCLC异种移植模型以及免疫功能的合成性NSCLC模型。在 这项工作的完成，我们希望提供适合进步的双MERTK/AXL选择性抑制剂 对于多种物种的GLP毒性研究，所有临床前验证研究都支持IND应用 描述了该化合物，是该化合物大规模合成的可行方法。