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 antigen.
Tumors create a nutrient-poor environment to support tumor growth. Enzymes that reduce the availability of tryptophan and arginine are IDO1 and ARG1, with both showing increased expression in tumor cells and suppressive cells like myeloid-derived suppressor cells (MDSCs). Thus, the nutrient-poor tumor microenvironment limits CD8 T cell responses and even can reduce the effectiveness of the checkpoint inhibitors, like anti-PD1, and other T-cell directed therapies. IDO1 and ARG1 inhibitors are currently in development as cancer immunotherapies to be used in combination with checkpoint inhibitors.
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.