Abstract
Indoleamine 2,3-dioxygenase (IDO1) is a key regulator of immune suppression by catalyzing the oxidation of L-tryptophan. IDO1 expression has been related to poor prognosis in several cancers and to resistance to checkpoint immunotherapies. We describe the characterization of a novel small molecule IDO1 inhibitor, NTRC 3883-0, in a panel of biochemical and cell-based assays, and various cancer models. NTRC 3883-0 released the inhibitory effect of IDO1 on CD8-positive T cell proliferation in co-cultures of IDO1-overexpressing cells with healthy donor lymphocytes, demonstrating its immune modulatory activity. In a syngeneic mouse model using IDO1-overexpressing B16F10 melanoma cells, NTRC 3883-0 effectively counteracted the IDO1-induced modulation of L-tryptophan and L-kynurenine levels, demonstrating its in vivo target modulation. Finally, we studied the expression and activity of IDO1 in primary cell cultures established from the malignant ascites of ovarian cancer patients. In these cultures, IDO1 expression was induced upon stimulation with IFNγ, and its activity could be inhibited by NTRC 3883-0. Based on these results, we propose the use of ascites cell-based functional assays for future patient stratification. Our results are discussed in light of the recent discontinuation of clinical trials of more advanced IDO1 inhibitors and the reconsideration of IDO1 as a valid drug target.
Highlights
The essential amino acid L-tryptophan (Trp) is an important regulator of cancer progression due to its regulatory role in immune cell activity [1, 2]
We have described the pharmacological characterization of a novel, selective IDO1 inhibitor, NTRC 3883-0, which was profiled in various biochemical and cell-based assays alongside epacadostat
To abolish the potential effect of the low and strongly variable IDO1 expression on the reliability of the efficacy model, we developed a syngeneic mouse model using B16F10 melanoma cells stably overexpressing mIDO1
Summary
The essential amino acid L-tryptophan (Trp) is an important regulator of cancer progression due to its regulatory role in immune cell activity [1, 2]. The catabolism of Trp is regulated by two distinct, evolutionary unrelated enzymes, indoleamine 2,3-dioxygenase 1 (IDO1) (EC 1.13.11.42), and tryptophan 2,3-dioxygenase (TDO) (EC 1.13.11.11) Both enzymes catalyze the oxidation of Trp, resulting in the formation of N-formyl kynurenine (NFK), which is rapidly converted into kynurenine (Kyn) by the enzyme kynurenine formamidase. IDO1 is broadly expressed at low levels in normal tissues [3], but is strongly induced by proinflammatory stimuli, such as IFNg [4]. TDO is constitutively expressed at high levels in the liver, where it functions to maintain Trp homeostasis [7] Consistent with this role, TDO has a relatively low affinity for Trp (KM,Trp, 190 μM) in comparison to IDO1 (KM,Trp, 6 μM) [8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
