Epacadostat (INCB024360)

Description

Epacadostat is an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1) with an IC₅₀ value of 7.1 nM in HeLa cells that demonstrates little activity against the related enzymes IDO2 or tryptophan 2,3-dioxygenase (TDO). It has been shown to promote T and natural killer-cell growth, to increase IFN-γ production, and to reduce conversion to regulatory T (Treg)-like cells in a coculture system of human allogeneic lymphocytes with either dendritic cells or tumor cells. Epacadostat can also inhibit tumor growth in tumor-bearing mice in a lymphocyte-dependent manner.

Uses

Epacadostat is a potent and novel indoleamine 2,3-dioxygenase (IDO1) inhibitor with IC50 of 10 nM. It has high selectivity over IDO2 and tryptophan 2,3-dioxygenase (TDO).

Synthesis

GENERAL STEPS: To a 20 L glass reactor was added N-[2-(4-[4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-ylamino)ethyl]sulfonamide (799.4 g, 1.72 mol) and tetrahydrofuran (3.2 L). The resulting solution was stirred at 20 °C for 7 min. Water (1.6 L) was then added. The reaction mixture was cooled to 2 °C and 30 wt% sodium hydroxide solution (475 mL, 666.4 g, 4.99 mol, 2.9 eq.) was added slowly over 8 min. The reaction mixture was warmed to 20 °C and kept at this temperature for 16 hours. Next, methyl tert-butyl ether (8.0 L) was added to the reaction mixture over 23 minutes. After addition of water (2.7 L), the reaction mixture was cooled to about 0°C. Subsequently, 85 wt% phosphoric acid (370.7 g, 3.22 mol, 1.9 eq.) was slowly added over 9 min. The reaction mixture was warmed to 20 °C and stirred for 1 hour. After standing and stratifying, the phases were separated. The organic phase was retained in the reactor and water (2.9 L) and 85 wt% phosphoric acid (370.7 g, 3.22 mol) were added and stirred at 20 °C for 1 hour. Layering was again allowed to stand and the phases were separated. The organic phase was retained in the reactor and water (3.2 L) was added and stirred at 20 °C for 1 hour. Leave to stratify and separate the phases. The organic phase was retained in the reactor and distilled under reduced pressure at 20 °C to remove 3.4 kg of distillate. Ethanol (4.8 L) was added to the residue and the mixture was distilled to a volume of 3.2 L. This distillation process was repeated once. Ethanol (0.6 L) was added to adjust the volume to 4 L. The reaction mixture was stirred at 20 °C for 16 h. Water (6.39 L) was subsequently added. The resulting slurry was stirred for 5 h at 20 °C. The product was collected by filtration and washed twice with a mixture of ethanol (529 mL) and water (1059 mL). The product was dried under reduced pressure at 45 °C for 65 h to afford the target compound (719.6 g, 95.4%) as a white solid.1H NMR (400 MHz, DMSO-d6): δ 11.51 (s, 1H), 8.90 (s, 1H), 7.17 (t, J = 8.8 Hz, 1H), 7.11 (dd, J = 6.1, 2.7 Hz, 1H), 6.76 (m, 1H), 6.71 (t, J = 6.0 Hz, 1H), 6.59 (s, 2H), 6.23 (t, J = 6.1 Hz, 1H), 3.35 (dd, J = 10.9, 7.0 Hz, 2H), 3.10 (dd, J = 12.1, 6.2 Hz, 2H); C11H13BrFN7O4S ( MW 438.23), LCMS (EI) m/e 437.9/439.9 (M+ + H).

in vivo

target

IDO1

IC 50

IDO1: 71.8 nM (IC₅₀)

References

[1] XIANGDONG LIU. Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity.[J]. Blood, 2010: 3520-3530. DOI:10.1182/blood-2009-09-246124
[2] HOLLY K KOBLISH. Hydroxyamidine inhibitors of indoleamine-2,3-dioxygenase potently suppress systemic tryptophan catabolism and the growth of IDO-expressing tumors.[J]. Molecular Cancer Therapeutics, 2010, 9 2: 489-498. DOI:10.1158/1535-7163.mct-09-0628
[3] CAROLINE JOCHEMS. The IDO1 selective inhibitor epacadostat enhances dendritic cell immunogenicity and lytic ability of tumor antigen-specific T cells.[J]. Oncotarget, 2016: 37762-37772. DOI:10.18632/oncotarget.9326
[4] SARAH YENTZ  David S. Indoleamine 2,3-Dioxygenase (IDO) Inhibition as a Strategy to Augment Cancer Immunotherapy.[J]. BioDrugs, 2018, 32 4: 311-317. DOI:10.1007/s40259-018-0291-4
[5] MAYANNE M T ZHU  Torsten O N  Amanda R Dancsok. Indoleamine Dioxygenase Inhibitors: Clinical Rationale and Current Development.[J]. Current Oncology Reports, 2019, 21 1: 2. DOI:10.1007/s11912-019-0750-1
[6] TARA C MITCHELL. Epacadostat Plus Pembrolizumab in Patients With Advanced Solid Tumors: Phase I Results From a Multicenter, Open-Label Phase I/II Trial (ECHO-202/KEYNOTE-037).[J]. Journal of Clinical Oncology, 2018, 36 32: 3223-3230. DOI:10.1200/jco.2018.78.9602