Epacadostat

Last updated
Epacadostat
Epacadostat.svg
Clinical data
ATC code
Identifiers
  • (Z)-N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-{[2-(sulfamoylamino)ethyl]amino}-1,2,5-oxadiazole-3-carboximidamide
CAS Number
DrugBank
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C11H13BrFN7O4S
Molar mass 438.23 g·mol−1
3D model (JSmol)
  • c1cc(c(cc1N/C(=N\O)/c2c(non2)NCCNS(=O)(=O)N)Br)F
  • 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)
  • Key:FBKMWOJEPMPVTQ-UHFFFAOYSA-N

Epacadostat (previously INCB24360) is an investigational drug for cancer. [1] Epacadostat is an inhibitor of indoleamine 2,3-dioxygenase-1 (IDO1). [1] [2] [3] Epacadostat inhibits IDO1 by competitively blocking it, without interfering with IDO2 or tryptophan 2,3-dioxygenase (TDO). It has antitumor activity in some models, though is most effective when combined with other immunotherapy agents. [4]

History and clinical trials

As of 2017, the combination of epacadostat with pembrolizumab (Keytruda) was being investigated by Incyte and Merck & Co. in several cancers, as was the combination of epacadostat with nivolumab (Opdivo) by Incyte and Bristol Myers Squibb. [5]

In April 2018, Incyte announced they were halting the Phase III ECHO-301/KEYNOTE-252 (NCT02752074) trial of epacadostat with pembrolizumab for melanoma as the combination therapy missed the first primary endpoint of improving progression-free survival vs. pembrolizumab alone. [6] [7] The second primary endpoint of overall survival is not yet determined. [6]

Related Research Articles

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<span class="mw-page-title-main">Indoleamine 2,3-dioxygenase</span> Mammalian protein found in Homo sapiens

Indoleamine-pyrrole 2,3-dioxygenase (IDO or INDO EC 1.13.11.52) is a heme-containing enzyme physiologically expressed in a number of tissues and cells, such as the small intestine, lungs, female genital tract or placenta. In humans is encoded by the IDO1 gene. IDO is involved in tryptophan metabolism. It is one of three enzymes that catalyze the first and rate-limiting step in the kynurenine pathway, the O2-dependent oxidation of L-tryptophan to N-formylkynurenine, the others being indolamine-2,3-dioxygenase 2 (IDO2) and tryptophan 2,3-dioxygenase (TDO). IDO is an important part of the immune system and plays a part in natural defense against various pathogens. It is produced by the cells in response to inflammation and has an immunosuppressive function because of its ability to limit T-cell function and engage mechanisms of immune tolerance. Emerging evidence suggests that IDO becomes activated during tumor development, helping malignant cells escape eradication by the immune system. Expression of IDO has been described in a number of types of cancer, such as acute myeloid leukemia, ovarian cancer or colorectal cancer. IDO is part of the malignant transformation process and plays a key role in suppressing the anti-tumor immune response in the body, so inhibiting it could increase the effect of chemotherapy as well as other immunotherapeutic protocols. Furthermore, there is data implicating a role for IDO1 in the modulation of vascular tone in conditions of inflammation via a novel pathway involving singlet oxygen.

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<span class="mw-page-title-main">Indoleamine 2,3-dioxygenase 2</span> Protein-coding gene in the species Homo sapiens

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References

  1. 1 2 "Epacadostat". NCI Drug Dictionary. National Cancer Institute. 2011-02-02.
  2. Brochez L, Chevolet I, Kruse V (May 2017). "The rationale of indoleamine 2,3-dioxygenase inhibition for cancer therapy". European Journal of Cancer. 76: 167–182. doi: 10.1016/j.ejca.2017.01.011 . PMID   28324751.
  3. Yue EW, Sparks R, Polam P, Modi D, Douty B, Wayland B, et al. (May 2017). "INCB24360 (Epacadostat), a Highly Potent and Selective Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitor for Immuno-oncology". ACS Medicinal Chemistry Letters. 8 (5): 486–491. doi:10.1021/acsmedchemlett.6b00391. PMC   5430407 . PMID   28523098.
  4. Van den Eynde BJ, van Baren N, Baurain JF (2020). "Is There a Clinical Future for IDO1 Inhibitors After the Failure of Epacadostat in Melanoma?". Annual Review of Cancer Biology. 4: 241–256. doi: 10.1146/annurev-cancerbio-030419-033635 .
  5. Staton T (3 April 2017). "Racing in lung cancer again (or still), Merck and BMS expand Incyte combo trials". FiercePharma.
  6. 1 2 "Incyte, Merck & Co. Halt Phase III Trial After Epacadostat/Keytruda Combination Fails in Melanoma". 6 April 2018.
  7. Walters J (6 April 2018). "Incyte Tumbles After Epacadostat Miss". BioCentury.