In order to mount an immune response against a tumor, CD8 T cells need a nutrient-rich environment. Access to the essential amino acids tryptophan and arginine are important for CD8 T cells to proliferate in response to T cell receptor engagement. Additionally, limiting tryptophan reduces CD8 T cells’ ability to respond to antigens.
IDO1 and ARG1 show increased expression in tumor cells and suppressive cells like myeloid-derived suppressor cells (MDSCs). They create a nutrient-poor tumor microenvironment which results in limiting CD8 T cell responses and reducing the effectiveness of the checkpoint inhibitors, like anti-PD1, and other T-cell directed therapies.
General control nonderepressible (GCN2) kinase is a stress response kinase that detects amino acid starvation within its environment. GCN2 plays a pivotal role in sensing the surrounding environment and in response to amino acid depletion, encourages T cell anergy (inactivation), T cell death and the proliferation of regulatory T cells (Treg) that suppress the immune response further.
Oral, Small Molecule GCN2 Inhibitors
We are developing orally-bioavailable, highly-selective GCN2 inhibitors that stimulate an immune response by limiting Treg and myeloid derived suppressor cell functions as well as encouraging effector T cell proliferation. While IDO1 and arginase inhibitors are currently in development, we believe a GCN2 inhibitor has the potential to be more efficacious as GCN2 is downstream of IDO1 and ARG1. 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 2018.