Aryl hydrocarbon Receptor (AHR) /
Amongst several factors that contribute to an immunosuppressive tumor environment, high levels of the tryptophan-degrading enzymes – IDO (Indoleamine 2,3-dioxygenase) and TDO (Tryptophan 2,3-dioxygenase) are outstanding. Both enzymes metabolize tryptophan into N-Formyl-kynurenine from which L-Kynurenine is formed. Kynurenine, Kynurenic acid (KA) and other secondary metabolites are endogenous activators of the Aryl hydrocarbon Receptor (AHR). AHR is a key orchestrator of the immune response and if activated by endogenous ligands like kynurenine and others, it can dampen the immune response in several cell types such as T-cells, myeloid cells, NK cells etc. This attenuation of the immune response is a natural homeostatic mechanism to prevent tissue damage, in particular in epithelial tissues such as the intestinal lining or the skin which are permanently exposed to pathogens such as bacteria and fungi.
From IDO inhibition towards AHR antagonisation
Cancer seems to hijack this mechanism by upregulating the Tryptophan-Kynurenine pathway through the overexpression of IDO, TDO, AHR or a combination of these three. IDO was first identified as an enzyme strongly correlating with an adverse outcome in cancer thus, many companies have developed IDO inhibitors. Despite initial positive results, the first IDO inhibitor in advanced clinical development, Epacadostat, failed to demonstrate benefits in a large-scale phase 3 trial in melanoma patients.
It was debated that this trial had several shortcomings but one straight-forward explanation is that tumors that overexpress TDO rather than IDO cannot be adequately targeted solely by IDO inhibitors.
This has been one of the reasons Phenex has decided to shift its research interests into the AHR pathway towards inhibiting AHR activation by antagonists, since AHR is clearly the downstream receptor of Kynurenine and its metabolites. First results from syngeneic mouse models with our AHR antagonists clearly show that this novel anti-tumor and immune-challenging mechanism has a stand-alone effect and can be combined with classical chemotherapy as well as immune checkpoint inhibitor therapy (Publications & Posters).
Phenex’ lead AHR antagonists show high potency, selectivity, favorable ADME/PK and are well tolerated, making them very attractive for clinical development.
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