The compounds certainly have different structures. The article you mention appears to be the one contains the following nugget, all but calling indoximod an IDO agonist: "Surprisingly incubation with 1-D-MT increased kyn production of human cancer cells. Cell-free assays revealed that 1-D-MT did not alter IDO1 enzymatic activity. Instead, 1-D-MT induced IDO1 mRNA and protein expression through pathways involving p38 MAPK and JNK signalling."
The Indoleamine-2,3-Dioxygenase (IDO) Inhibitor 1-Methyl-D-tryptophan Upregulates IDO1 in Human Cancer Cells
An indirect response came after a year or so:
IDO inhibits a tryptophan sufficiency signal that stimulates mTOR A novel IDO effector pathway targeted by D-1-methyl-tryptophan
So, I get what MZ and AF are saying. Indoximod seems to work by by targeting an indirect effect of IDO, rather than by inhibiting IDO itself. But the authors of the second article, which includes NewLink personnel, do take a swipe at the direct IDO inhibitors: " . . . we showed that the IDO pathway inhibitor D-1MT acts as a Trp mimetic in regulating mTOR. This finding offers a seminal advance in the understanding of the mechanism of action of this experimental agent, which is currently being investigated in Phase IB/II clinical trials. Additionally, it illustrates the mechanistic distinctions between D-1MT and direct enzymatic inhibitors of IDO, the clinical development of which may pose greater safety risks, 17 particularly in the setting of combinatorial therapies, given their general rather than subtle disruption of IDO function."
But in a subsequent article -still including one NewLink researcher - they say "Fourth, Ido1-deficient mice are viable and healthy [ 78] and their careful examination argues that while IDO inhibitors will exhibit some side-effects, they are unlikely to pose unmanageable mechanism-based toxicities [ 79]."
From: Indoleamine 2,3-dioxygenase pathways of pathgenic inflammation and immune escape in cancer
Guess what? Footnotes 17 and 79 are cites of the same article. Hmmm.
And I gather navoximod, returned by Genentech, is a direct inhibitor. It is, of course, well behind epacadostat.
Meanwhile, thought about bailing for burger money; missed my chance while digging around. :>(
Cheers, Tuck |
