Immune checkpoint proteins suppress the immune system and thereby prevent an appropriate immune response to tumor cell growth resulting in a variety of cancers. Several approved antibody drugs targeting immune checkpoints have demonstrated promising benefit in treating cancer by stimulating an immune response to cancer cells. Ensemble has developed small molecule inhibitors that may complement current antibody therapies and may provide unique advantages to modulating an immune response to cancer cells. These advantages include:
- Safety: the shorter half-lives of small molecules minimize the duration of adverse events
- Efficacy: small molecules will penetrate solid tumors better than antibodies
- Administration: small molecules provide potential for oral and other non-injectable routes
Indoleamine 2,3-dioxygenase 1 (IDO-1) is an intracellular immune checkpoint protein that catalyzes the breakdown of the essential amino acid tryptophan. Dysregulation of this enzyme can result in the suppression of an appropriate immune response by macrophages and T-cells to cancer. Inhibition of IDO-1 has been shown to reinvigorate the natural immune response to cancer cells, and could have utility in diverse forms of cancer such as metastatic melanoma and lung cancer.
Ensemble has used its drug discovery platform to find novel, orally bioavailable, potent and specific IDO-1 inhibitors. The compounds bind to an allosteric site on the enzyme rather than the heme-containing catalytic site. In this way highly potent and selective inhibitors have been identified that will avoid possible toxicity associated with non-specific heme binding. Ensemble is optimizing this series towards development candidate status.