Epacadostat

Description: Epacadostat/ INCB24360 is an inhibitor of indoleamine 2,3-dioxygenase-1) (IDO1). An investigational drug for cancer in phase 3.

• Catalog: OFC1204669588
• CAS: 1204669-58-8
• Category: Fluorinated APIs
• Synonyms: INCB24360
• Purity: 98%

• IUPAC Name: N'-(3-bromo-4-fluorophenyl)-N-hydroxy-4-[2-(sulfamoylamino)ethylamino]-1,2,5-oxadiazole-3-carboximidamide
• InChI: InChI=1S/C11H13BrFN7O4S/c12-7-5-6(1-2-8(7)13)17-11(18-21)9-10(20-24-19-9)15-3-4-16-25(14,22)23/h1-2,5,16,21H,3-4H2,(H,15,20)(H,17,18)(H2,14,22,23)
• InChI Key: FBKMWOJEPMPVTQ-UHFFFAOYSA-N
• Isomeric SMILES: C1=CC(=C(C=C1N=C(C2=NON=C2NCCNS(=O)(=O)N)NO)Br)F
• EC Number: 815-121-1

• Molecular Formula: C11H13BrFN7O4S
• Molecular Weight: 438.23

• XLogP3-AA: 0.8
• Hydrogen Bond Donor Count: 5
• Hydrogen Bond Acceptor Count: 11
• Rotatable Bond Count: 8
• Exact Mass: 436.99171 g/mol
• Monoisotopic Mass: 436.99171 g/mol
• Topological Polar Surface Area: 176Ų
• Heavy Atom Count: 25
• Formal Charge: 0
• Complexity: 563

Case Study

Epacadostat for the Experimental Treatment of Recurrent Ovarian Clear Cell Carcinoma

Gien LT, et al. Gynecologic Oncology, 2024, 186, 61-68.

This phase II, single-arm study investigated epacadostat, an IDO-1 inhibitor, in combination with pembrolizumab for patients with recurrent ovarian clear cell carcinoma (OCCC). Fourteen patients with measurable disease and 1-3 prior treatment regimens received oral epacadostat 100 mg twice daily alongside intravenous pembrolizumab 200 mg every 3 weeks. The primary endpoint was overall response rate (ORR), with secondary endpoints including progression-free survival (PFS), overall survival (OS), and safety assessment. Tumor responses were evaluated radiographically every 8-12 weeks. The combination achieved an ORR of 21% and a disease control rate of 50%, with median PFS of 4.8 months and OS of 18.9 months. Grade ≥3 adverse events primarily involved electrolyte disturbances and gastrointestinal symptoms. This study highlights the practical application of epacadostat in immunomodulatory combination therapy for OCCC.

Epacadostat for Chemo-Immunotherapy in B16F10 Melanoma Models

Khoshkhabar R, et al. International Immunopharmacology, 2024, 137, 112437.

This study evaluated the experimental application of Epacadostat (EPA), a potent IDO1 inhibitor, in combination with Docetaxel (DTX) for melanoma therapy. In vitro, B16F10 cells and NIH fibroblasts were treated with varying concentrations of EPA and DTX, and synergistic cytotoxicity was quantified using the combination index (CI) based on the unified theory. In vivo, murine B16F10 tumor-bearing models received nano-liposomal Epacadostat (Lip-EPA) with Docetaxel, and tumor growth, lifespan, and immune modulation were assessed. Immune profiling included T-cell infiltration, CTL and TIL populations, IFN-γ release, Treg counts, and IL-10 levels. Histopathology quantified tryptophan (Trp) and kynurenine (Kyn) levels. Results demonstrated a 69.15% tumor growth reduction, ILS > 47.83%, enhanced CTL/TIL infiltration, and restoration of Trp/Kyn balance, confirming Lip-EPA's synergistic immuno-therapeutic effect.

Liposomal Epacadostat for Enhanced Antitumor Efficacy in Melanoma Models

Tahaghoghi-Hajghorbani S, et al. European Journal of Pharmaceutical Sciences, 2021, 165, 105954.

A novel liposomal formulation of Epacadostat (EPA) was developed to enhance its therapeutic efficacy against melanoma while minimizing dosage and side effects. EPA was encapsulated using a remote loading method, and the resulting liposomes were characterized for particle size (128.1 ± 1.1 nm), zeta potential (-16.5 ± 1 mV), and encapsulation efficiency (64.9 ± 3.5%). A validated UV-visible spectrophotometric assay following ICH Q2B guidelines ensured precise and robust quantification of EPA within liposomes. In vitro studies demonstrated that liposomal EPA exhibited a lower IC50 (64 ng/mL) compared with free EPA (128 ng/mL). In vivo, B16F10 melanoma-bearing C57BL/6 mice treated with liposomal EPA showed slower tumor progression and improved survival, highlighting the formulation's potential as an immunotherapeutic agent.

Targeted Tumor Exposure and Pharmacodynamic Evaluation of Epacadostat in CT26 Mouse Model

Poncelet L, et al. Journal of Pharmaceutical and Biomedical Analysis, 2019, 170, 220-227.

This study investigates the experimental application of the IDO1 inhibitor Epacadostat in the CT26 mouse tumor model using advanced analytical techniques. Quantitative Mass Spectrometry Imaging (QMSI) and LC-MS/MS were employed to map drug distribution and monitor endogenous metabolite levels within the tumor microenvironment. Results demonstrated that 61% of Epacadostat localized within 38% of the tumor surface, correlating positively with IDO1 expression. Pharmacodynamic effects were assessed via kynurenine/tryptophan (Kyn/Trp) ratio, revealing substantial decreases in treated tumors (-82%), plasma (-63%), and blood (-62%) relative to controls. Regional analysis further indicated differential Kyn accumulation corresponding to local Epacadostat exposure. This integrated experimental approach highlights Epacadostat's site-specific activity and provides a robust framework for evaluating intra-tumor drug efficacy in immuno-oncology research.