Oncology
DA-4505
Unmet needs
- The Kynurenine pathway has been identified as crucial mechanisms in cancer immune escape. The conversion of Tryptophan into Kynurenine by IDO1/IDO2/TDO promotes the development of an immunosuppressive microenvironment and inhibits anti-tumor immune responses.
- As Indoleamine 2, 3-dioxygenase 1 (IDO1) has emerged as a promising target for cancer immune therapy, IDO1 inhibitors has been developed by a number of companies. However, the failure of a phase III clinical trial with the IDO1 inhibitor, Epacadostat, posed the need for in-depth insights into the Kynurenine pathway.
- Several potential therapeutic targets have been investigated to overcome the limitation of IDO1 inhibitors. Among them, Aryl hydrocarbon Receptor(AhR) and GCN2 could be attractive targets which are directly related with high level of Kyn and low level of Trp, respectively. We are anticipating that each of targets directly inhibits immunosuppressive effects within the tumor microenvironment(TME).
MoA
(Mechanism of Action)
- AhR is a ligand activated transcription factor that regulates the activity of multiple innate and adaptive immunity. Its activation by Trp metabolites, such as kynurenine, inhibits immune activation mechanisms in T lymphocytes, macrophages, and dendritic cells.
- DA-4505 is a potent and selective small molecule AhR inhibitor selected based on the MoA study and antitumor activity in reclinical models. In particular, AhR is also known to up-regulate PD-1 on CD8+ T cells. Therefore we expect DA-4505 to overcome the immunosuppressive effects driving resistance to anti-PD-1/PD-L1 in certain subsets of cancer patients. The combination of DA-4505 and anti-PD-1 showed robust antitumor activity in some preclinical models, suggesting that DA-4505 has the potential in the treatment of solid tumors.
