The high proliferative rates of tumor cells and the infiltration of myeloid cells into the tumor results in the depletion of nutrients such as amino acids. This metabolically stressful environment causes the activation of a well conserved nutrient preservation pathway which slows down the immune response and causes breakdown of parts of the cell to generate nutrients in a process called autophagy. This pathway therefore helps the tumor by maintaining nutrient levels while blocking the immune response to it, thereby accelerating tumor growth. A key component of this nutrient preservation pathway is a protein kinase called General Control Nonderepressible 2 (GCN2). GCN2 switches on when it detects a reduction of amino acid and it’s activity results in T cell anergy (inactivation), T cell death, the proliferation of Regulatory T (Treg) cells, and the potentiation of myeloid-derived suppressor cells (MDSC). Blocking the activity of GCN2 with a small molecule inhibitor would be expected to reinvigorate the immune response allowing T cells to proliferate and kill tumor cells.
Oral, Small Molecule GCN2 Inhibitors
We are developing orally-bioavailable, highly-selective GCN2 inhibitors that stimulate an immune response by limiting Treg and MDSC functions as well as encouraging effector T cell proliferation. We believe a GCN2 inhibitor has the potential to be highly efficacious since this key protein acts downstream of multiple tumor-promoting enzymes such as indoleamine deoxygenase (IDO) and arginase (ARG), which breakdown the amino acids tryptophan and arginine, respectively. In cell-based assays, our GCN2 inhibitors increase CD8 T cell proliferation in tryptophan- or arginine-limited conditions. Additional preclinical activities are ongoing for this series of compounds.
We expect to select a preclinical candidate in early 2019.