PF-06840003

A novel potent, selective, orally active, and CNS penetrant IDO-1 inhibitor with IC50 of 0.41 uM for hIDO-1; weakly inhibits hTDO-2 with IC50 of 140 uM, and shows no activity against hIDO-2 (>100 uM); shows activity both in the HeLa assay (IC50=1.8 uM) as well as in the LPS/INFγ-stimulated THP1 cells (IC50=1.7 uM), maintains good efficiency in the whole blood assay (IC50=4.7 uM); shown significant antitumor activity in mice and very favorable ADME profile.Brain Cancer Phase 1 Clinical(In Vitro):PF-06840003 reverses IDO-1-induced T-cell anergy in vitro. PF-06840003 shows activity both in the HeLa assay (IC50=1.8 μM) as well as in the LPS/ INFγ-stimulated THP1 cells (IC50=1.7 μM).(In Vivo):PF-06840003 reduces intratumoral kynurenine levels in mice by >80% and inhibits tumor growth in multiple preclinical syngeneic models in mice, in combination with immune checkpoint inhibitors. PF-0684003 has favorable predicted human pharmacokinetic properties, including a predicted t1/2 of 16-19 hours.