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

MerTK和Ax1是(Tyro3，Ax1，MERTK)受体酪氨酸激酶家族的成员，它们是 在癌细胞中异常表达，在那里它们的功能是促进细胞存活。MERTK和AXL都进行了调解 对多种细胞毒性化疗药物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发挥抑制抗肿瘤作用的先天免疫细胞 免疫，导致肿瘤生长和转移增强。这些数据和其他数据牵涉到MERTK和AXL 作为治疗多种人类肿瘤的靶点。此外，由于MERTK的致癌作用 和axl在肿瘤细胞和免疫细胞中，抑制剂有望通过两者介导的抗肿瘤作用。 直接杀伤肿瘤细胞和调节先天免疫反应。众多小分子抑制剂和 针对Ax1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。 尽管最初的反应强劲，但针对单个致癌驱动因素的TKI的临床疗效历来 因获得性突变或代偿性旁路激活而产生抵抗力而受限 发信号。共享共同下游信号通路的密切相关蛋白质通常可以提供旁路 信号传递，从而调节抗性。事实上，MERTK介导了对Axl抑制剂的耐药性，反之亦然。 提示至少在某些情况下，双重抑制MERTK和Axl可能是一种更有效的治疗方法 策略优于MERTK或AXL单独抑制。与这一假设一致的是，MERTK和Axl抑制剂 在多种上皮性癌症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，它们在多种治疗耐药中的作用，以及它们在 肿瘤细胞和先天免疫系统支持同时针对MERTK和AXL的药物的发展。至 日期，INCB081776是唯一描述的双MERTK/AXL TKI；然而， 化合物尚未公开披露。 我们之前已经开发和优化了MERTK选择性TKIs。我们假设在某些情况下是双重的 MerTK和Axl抑制剂对非小细胞肺癌和其他癌症的治疗将比靶向药物更有效 MerTK或AXL单独使用。在这里，我们建议使用一种新的计算方法来结合 酶学、细胞学和药效学分析，以开发新的、有效的和选择性的双重MERTK和 AXL抑制剂及其在MERTK和AXL依赖中的生化和功能活性验证 皮下和原位非小细胞肺癌异种移植模型和免疫活性同基因非小细胞肺癌模型。在… 这项工作的完成，我们希望提供一种双重MERTK/Axl选择性抑制剂适用于先进 对于多个物种的GLP毒性研究，所有支持IND应用的临床前验证研究 描述了该化合物，以及大规模合成该化合物的可行方法。

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.