Navoximod

Navoximod (NLG- 919, GDC-0919) is a potent indoleamine- (2,3) -dioxygenase (IDO) pathway inhibitor (Ki/EC50: 7 nM/75 nM) . (In Vitro) :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. 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 . (In Vivo) :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 ~50%. In vivo, in mice bearing large established B16F10 tumors, administration of Navoximod markedly enhances the anti-tumor responses of na ve, resting pmel-1 cells to vaccination with cognate hgp100 peptide plus CpG-1826 in IFA. In this stringent established-tumor model, Navoximod plus pmel-1/vaccine produce a dramatic collapse of tumor size within 4 days of vaccination (~95% reduction in tumor volume compare to control animals receiving pmel-1/vaccine alone without Navoximod) . When combined with NSC 362856 (TMZ) +radiation therapy (RT), both Navoximod and D-1MT (Indoximod) enhance survival relative to mice treated with TMZ+RT alone.