Background:

Navoximod (GDC-0919; NLG-919) is a potent IDO (indoleamine-(2,3)-dioxygenase) pathway inhibitor with Ki/EC50 of 7 nM/75 nM.
Using IDO-expressing human monocyte-derived dendritic cells (DCs) in allogeneic mixed lymphocyte reaction (MLR) reactions, Navoximod (NLG919) potently blocks IDO-induced T cell suppression and restores robust T cell responses with an ED50=80 nM. Similarly, using IDO-expressing mouse DCs from tumor-draining lymph nodes, Navoximod abrogates IDO-induced suppression of antigen-specific T cells (OT-I) in vitro, with ED50=120 nM[1]. Navoximod inhibits the IDO activity in a concentration-dependent manner with an EC50 of 0.95?μM. PEG2k-Fmoc-NLG(L) is less active (EC50 of 3.4?μM) in inhibiting IDO compared with free Navoximod while PEG2k-Fmoc-NLG(S) is least active (EC50>10?μM). Coculture of IDO+tumor cells with splenocytes isolated from BALB/c mice leads to significant inhibition of T-cell proliferation. This inhibition is significantly attenuated when the mixed cells are treated with Navoximod. PEG2k-Fmoc-NLG(L) is also active in reversing the inhibitory effect of tumour cells although slightly less potent than Navoximod [3].
VNavoximod (NLG919) is orally bioavailable (F>70%); and has a favorable pharmacokinetic and toxicity profile. In mice, a single oral administration of Navoximod reduces the concentration of plasma and tissue Kyn by