Highly selective for GCN2, CRD-1968099 is a first-in-class orally available GCN2 inhibitor.
CRD-1968099 may exhibit anti-tumor effects in pre-clinical models by adding excessive RNA deregulation stress through the accumulation of aberrant tRNAs.
In addition to inducing aberrant tRNA, CRD-1968099 has the potential to enhance the tumor immune effects of immune checkpoint inhibitors, such as anti-PD-1 antibodies, by eliminating myeloid-derived suppressor cells (MDSCs), which suppress T cell functions responsible for tumor immunity.
Amino acids, one of the most important nutrients for living organisms, bind to tRNA and are transported to ribosomes, the site of protein synthesis, where protein synthesis takes place.
In situations of amino acid deficiency, aberrant tRNAs not bound to amino acids accumulate. In the tumor microenvironment, the development of abnormal blood vessels results in inadequate blood supply, causing deficiencies of amino acids and other nutrients.
Thus, cancer cells use GCN2 kinase to sense nutrient deficiency conditions and avoid and adapt to the accumulation of aberrant tRNAs.
GCN2 is a serine/threonine protein kinase that senses amino acid deficiency by binding to an uncharged aberrant tRNA that accumulates in situations of amino acid deficiency.
The accumulation of uncharged tRNAs and subsequent activation of GCN2 promote amino acid uptake and new synthesis via phosphorylation of the substrate EIF2α, thereby avoiding amino acid deficiency.
Inhibition of GCN2 under amino acid deficiency may be one of the causes of RNA deregulation stress by leading to the accumulation of aberrant tRNA.
GCN2 is also thought to function as an important suppressor of anti-tumor immunity. Inhibition of GCN2 has the potential to enhance anti-tumor immunity by CD8+ T cells because it suppresses the function of MDSCs, which act in a suppressive manner against tumor immunity.
