Navoximod

Navoximod (GDC-0919; NLG-?919) is a potent IDO (indoleamine-(2,3)-dioxygenase) pathway inhibitor with K_i/EC₅₀ of 7 nM/75 nM. IC50 & Target: EC50: 75 nM (IDO)^[1]
Ki: 7 nM (IDO)^[1] 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^[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]. 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)^[1]. 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^[2].