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.
Approximately two-thirds of patients diagnosed with cancer in the United States will be cured of their disease using a combination of surgery, radiation and chemotherapy, but progress towards enhanced survival in adults with advanced and metastatic disease has been painfully slow, even in the era of targeted therapies, and new, more effective therapies are desperately needed. MERTK and AXL, members of the TAM-family of receptor tyrosine kinases, are aberrantly expressed in a wide variety of different tumor types and are potential therapeutic targets in majority of human tumors, therefore, agents targeting both MERTK and AXL may be particularly effective. The studies described here aim to develop potent and selective dual MERTK and AXL inhibitors suitable for clinical application and as such, may have a direct impact on outcomes and/or quality of life for patients with advanced cancers.
