WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 205493
CAS#: 914471-09-3 (INCB024360-analog)
Description: INCB024360-analog, also known as IDO-IN-2 with CAS#914471-09-3, is a potent and orally available hydroxyamidine and inhibitor of indoleamine 2,3-dioxygenase (IDO1) with potential immunomodulating and antineoplastic activities. INCB024360-analog is a potent (HeLa IC50=19 nM) competitive inhibitor of IDO. Testing of INCB024360-analog in mice demonstrated pharmacodynamic inhibition of IDO, as measured by decreased kynurenine levels (>50%) in plasma and dose dependent efficacy. Note: MedKoo CAT#206461, INCB024360 has CAS#1204669-58-8 (http://www.medkoo.com/products/6778)
MedKoo Cat#: 205493
CAS#: 914471-09-3 (INCB024360-analog)
Chemical Formula: C9H7ClFN5O2
Exact Mass: 271.02723
Molecular Weight: 271.63
Elemental Analysis: C, 39.79; H, 2.60; Cl, 13.05; F, 6.99; N, 25.78; O, 11.78
Synonym: INCB024360-analog; INCB24360-analog; Epacadostat-analog. IDO-IN-2
IUPAC/Chemical Name: 4-amino-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1,2,5-oxadiazole-3-carboximidamide
InChi Key: HGXSLPIXNPASGZ-UHFFFAOYSA-N
InChi Code: InChI=1S/C9H7ClFN5O2/c10-5-3-4(1-2-6(5)11)13-9(14-17)7-8(12)16-18-15-7/h1-3,17H,(H2,12,16)(H,13,14)
SMILES Code: O/N=C(C1=NON=C1N)/NC2=CC=C(F)C(Cl)=C2
INCB024360-Analog is structurally related to Epacadostat (INCB024360). Before middle of 2015, some database (e.g, pubchem CID#11978742) mistakenly listed INCB024360 structure as CAS#914471-09-3, many reagent suppliers included MedKoo used pubchem's structure and sold CAS#914471-09-3 as INCB024360. By middle of 2015, J. Med. Chem (Dounay AB, et al, and Röhrig UF et al ), Sci-Finder and other database (such as ChemIDplus) published the chemical structure of INCB024360, which has CAS#1204669-58-8. Based on the above information, MedKoo decided to re-name Cat#205493, CAS#914471-09-3 as INCB024360-Analog. However, as of August 20, 2015, there are still many reagent companies to sell the wrong INCB024360, which structure was actually CAS#914471-09-3 (or INCB024360-Analog). Customer can email or call MedKoo to clarify the structure issue related to INCB024360. (last updated: 12/21/2015).
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INCB024360-Analog was first reported in J. Med. Chem. 2009, 52, 7364–7367.
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Indoleamine 2,3-dioxygenase-1 (IDO1; IDO) mediates oxidative cleavage of tryptophan, an amino acid essential for cell proliferation and survival. IDO1 inhibition is proposed to have therapeutic potential in immunodeficiency-associated abnormalities, including cancer. INCB024360 is a novel IDO1 inhibitor. In cellular assays, INCB024360 selectively inhibits human IDO1 with IC(50) values of approximately 10nM, demonstrating little activity against other related enzymes such as IDO2 or tryptophan 2,3-dioxygenase (TDO). In coculture systems of human allogeneic lymphocytes with dendritic cells (DCs) or tumor cells, INCB024360 inhibition of IDO1 promotes T and natural killer (NK)-cell growth, increases IFN-gamma production, and reduces conversion to regulatory T (T(reg))-like cells. IDO1 induction triggers DC apoptosis, whereas INCB024360 reverses this and increases the number of CD86(high) DCs, potentially representing a novel mechanism by which IDO1 inhibition activates T cells. Furthermore, IDO1 regulation differs in DCs versus tumor cells. Consistent with its effects in vitro, administration of INCB024360 to tumor-bearing mice significantly inhibits tumor growth in a lymphocyte-dependent manner. Collectively, the data suggest that selective inhibition of IDO1 may represent an attractive cancer therapeutic strategy via up-regulation of cellular immunity.(Blood. 2010 Apr 29;115(17):3520-30. ).
1: Yue EW, Sparks R, Polam P, Modi D, Douty B, Wayland B, Glass B, Takvorian A, Glenn J, Zhu W, Bower M, Liu X, Leffet L, Wang Q, Bowman KJ, Hansbury MJ, Wei M, Li Y, Wynn R, Burn TC, Koblish HK, Fridman JS, Emm T, Scherle PA, Metcalf B, Combs AP. INCB24360 (Epacadostat), a Highly Potent and Selective Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitor for Immuno-oncology. ACS Med Chem Lett. 2017 Mar 6;8(5):486-491. doi: 10.1021/acsmedchemlett.6b00391. eCollection 2017 May 11. PubMed PMID: 28523098; PubMed Central PMCID: PMC5430407.
2: Wu Y, Xu T, Liu J, Ding K, Xu J. Structural insights into the binding mechanism of IDO1 with hydroxylamidine based inhibitor INCB14943. Biochem Biophys Res Commun. 2017 May 27;487(2):339-343. doi: 10.1016/j.bbrc.2017.04.061. Epub 2017 Apr 13. PubMed PMID: 28412361.
3: Maliniemi P, Laukkanen K, Väkevä L, Dettmer K, Lipsanen T, Jeskanen L, Bessede A, Oefner PJ, Kadin ME, Ranki A. Biological and clinical significance of tryptophan-catabolizing enzymes in cutaneous T-cell lymphomas. Oncoimmunology. 2017 Feb 10;6(3):e1273310. doi: 10.1080/2162402X.2016.1273310. eCollection 2017. PubMed PMID: 28405495; PubMed Central PMCID: PMC5384345.
4: Brochez L, Chevolet I, Kruse V. The rationale of indoleamine 2,3-dioxygenase inhibition for cancer therapy. Eur J Cancer. 2017 May;76:167-182. doi: 10.1016/j.ejca.2017.01.011. Epub 2017 Mar 18. Review. PubMed PMID: 28324751.
5: Zhang Q, Zhang Y, Boer J, Shi JG, Hu P, Diamond S, Yeleswaram S. In Vitro Interactions of Epacadostat and its Major Metabolites with Human Efflux and Uptake Transporters: Implications for Pharmacokinetics and Drug Interactions. Drug Metab Dispos. 2017 Jun;45(6):612-623. doi: 10.1124/dmd.116.074609. Epub 2017 Mar 10. PubMed PMID: 28283500.
6: Beatty GL, O'Dwyer PJ, Clark J, Shi JG, Bowman KJ, Scherle PA, Newton RC, Schaub R, Maleski J, Leopold L, Gajewski TF. First-in-Human Phase I Study of the Oral Inhibitor of Indoleamine 2,3-Dioxygenase-1 Epacadostat (INCB024360) in Patients with Advanced Solid Malignancies. Clin Cancer Res. 2017 Jan 4. doi: 10.1158/1078-0432.CCR-16-2272. [Epub ahead of print] PubMed PMID: 28053021.
7: Shi JG, Bowman KJ, Chen X, Maleski J, Leopold L, Yeleswaram S. Population Pharmacokinetic and Pharmacodynamic Modeling of Epacadostat in Patients With Advanced Solid Malignancies. J Clin Pharmacol. 2017 Jun;57(6):720-729. doi: 10.1002/jcph.855. Epub 2016 Dec 19. PubMed PMID: 27990653.
8: Jochems C, Fantini M, Fernando RI, Kwilas AR, Donahue RN, Lepone LM, Grenga I, Kim YS, Brechbiel MW, Gulley JL, Madan RA, Heery CR, Hodge JW, Newton R, Schlom J, Tsang KY. The IDO1 selective inhibitor epacadostat enhances dendritic cell immunogenicity and lytic ability of tumor antigen-specific T cells. Oncotarget. 2016 Jun 21;7(25):37762-37772. doi: 10.18632/oncotarget.9326. PubMed PMID: 27192116; PubMed Central PMCID: PMC5122347.
9: Boer J, Young-Sciame R, Lee F, Bowman KJ, Yang X, Shi JG, Nedza FM, Frietze W, Galya L, Combs AP, Yeleswaram S, Diamond S. Roles of UGT, P450, and Gut Microbiota in the Metabolism of Epacadostat in Humans. Drug Metab Dispos. 2016 Oct;44(10):1668-74. doi: 10.1124/dmd.116.070680. Epub 2016 Jul 25. PubMed PMID: 27457784.
10: Dhiman V, Giri KK, S SP, Zainuddin M, Rajagopal S, Mullangi R. Determination of epacadostat, a novel IDO1 inhibitor in mouse plasma by LC-MS/MS and its application to a pharmacokinetic study in mice. Biomed Chromatogr. 2017 Feb;31(2). doi: 10.1002/bmc.3794. Epub 2016 Aug 11. PubMed PMID: 27451018.
11: Shi JG, Chen X, Punwani NG, Williams WV, Yeleswaram S. Potential Underprediction of Warfarin Drug Interaction From Conventional Interaction Studies and Risk Mitigation: A Case Study With Epacadostat, an IDO1 Inhibitor. J Clin Pharmacol. 2016 Nov;56(11):1344-1354. doi: 10.1002/jcph.737. PubMed PMID: 26990117.
12: Zhai L, Spranger S, Binder DC, Gritsina G, Lauing KL, Giles FJ, Wainwright DA. Molecular Pathways: Targeting IDO1 and Other Tryptophan Dioxygenases for Cancer Immunotherapy. Clin Cancer Res. 2015 Dec 15;21(24):5427-33. doi: 10.1158/1078-0432.CCR-15-0420. Epub 2015 Oct 30. Review. PubMed PMID: 26519060; PubMed Central PMCID: PMC4681601.
13: Vacchelli E, Aranda F, Eggermont A, Sautès-Fridman C, Tartour E, Kennedy EP, Platten M, Zitvogel L, Kroemer G, Galluzzi L. Trial watch: IDO inhibitors in cancer therapy. Oncoimmunology. 2014 Dec 15;3(10):e957994. eCollection 2014 Nov. Review. PubMed PMID: 25941578; PubMed Central PMCID: PMC4292223.
14: Liu X, Shin N, Koblish HK, Yang G, Wang Q, Wang K, Leffet L, Hansbury MJ, Thomas B, Rupar M, Waeltz P, Bowman KJ, Polam P, Sparks RB, Yue EW, Li Y, Wynn R, Fridman JS, Burn TC, Combs AP, Newton RC, Scherle PA. Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity. Blood. 2010 Apr 29;115(17):3520-30. doi: 10.1182/blood-2009-09-246124. Epub 2010 Mar 2. PubMed PMID: 20197554.
15: Koblish HK, Hansbury MJ, Bowman KJ, Yang G, Neilan CL, Haley PJ, Burn TC, Waeltz P, Sparks RB, Yue EW, Combs AP, Scherle PA, Vaddi K, Fridman JS. Hydroxyamidine inhibitors of indoleamine-2,3-dioxygenase potently suppress systemic tryptophan catabolism and the growth of IDO-expressing tumors. Mol Cancer Ther. 2010 Feb;9(2):489-98. doi: 10.1158/1535-7163.MCT-09-0628. Epub 2010 Feb 2. PubMed PMID: 20124451.