TAM kinases are essential negative regulators of the immune system and function at the interface of innate and adaptive immunity. Three independent mechanisms utilized by TAM family receptor tyrosine kinase to fuel tumor growth include: (1). Tumours educate tumour-infiltrating lymphocytes (TILs) to up-regulate GAS6 expression, which in turn stimulates the tumor growth by the activation of oncogenic TAM signaling in tumor cells. (2). Activation of MER in tumor-associated macrophages leads to an immunosuppressive cytokine environment, decreased antitumor CD8+ cytotoxic T cell responses, and increased tumor growth. (3). TAM inhibits inflammation in dendritic cells and macrophages by promoting the phagocytosis of apoptotic cells, stimulating the maturation of natural killer cells, and down-regulating the production of pro-inflammatory cytokines.
Therefore, TAM kinase inhibition is anticipated not only to suppress cancer cell survival, overcome chemo-resistance, and diminish metastatic potential, but more importantly enhance anti-tumour immunity.
SLC has identified a number of structurally distinct chemical scaffolds as TAM family kinase inhibitors. We are currently in the process of evaluation of these scaffolds and anticipate to select a lead scaffold into the lead optimization stage by the end of 2018.
Macrophage colony-stimulating factor 1 receptor (CSF-1R) regulates proliferation, survival and differentiation of hematopoietic precursor cells such as monocytes and macrophages. It promotes the release of pro-inflammatory chemokines in response to IL34 and CSF1, and thereby plays an important role in innate immunity and in inflammatory processes.
SLC has identified a number of chemical scaffolds that inhibit CSF-1R activity. We plan to evaluate these scaffolds and anticipate to select a lead scaffold to enter the lead optimization stage by Q2, 2019.
RON (or Macrophage-stimulating protein-1 receptor, MST1R) is a receptor tyrosine kinase closely related to cMET, but with highly differentiated biology that is central in control of the macrophage population and enhancement of host immune surveillance and defuses macrophage pro-inflammatory responses. It is overexpressed in a range of solid tumour types and highly expressed in macrophages. It also plays a role in the innate immune response by regulating the migration and phagocytic activity of macrophages. Many tumour cell types express its ligand, MSP. In addition, RON activation in tumour cells promotes aggressive disease, early metastasis and preferential metastasis to bone and bone loss via upregulation of osteoclast function.
SLC has identified a number of chemical scaffolds that inhibit RON activity. We plan to evaluate these scaffolds and anticipate to select a lead scaffold to enter the lead optimization stage by end of 2019.