Synonym
INCB39110; INCB 39110; INCB-39110; INCB039110; INCB-039110; INCB 039110; Itacitinib; 1334298-96-2
IUPAC/Chemical Name
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile
InChi Key
KTBSXLIQKWEBRB-UHFFFAOYSA-N
InChi Code
InChI=1S/C26H23F4N9O/c27-20-18(1-7-32-22(20)26(28,29)30)24(40)37-9-3-17(4-10-37)38-13-25(14-38,5-6-31)39-12-16(11-36-39)21-19-2-8-33-23(19)35-15-34-21/h1-2,7-8,11-12,15,17H,3-5,9-10,13-14H2,(H,33,34,35)
SMILES Code
N#CCC1(N2N=CC(C3=C4C(NC=C4)=NC=N3)=C2)CN(C5CCN(C(C6=C(F)C(C(F)(F)F)=NC=C6)=O)CC5)C1
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO, not in water
Shelf Life
>2 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
Biological target:
Itacitinib (INCB039110) is an orally active and selective inhibitor of JAK1 with an IC50 of 2 nM for human JAK1 and shows >20-fold selectivity for JAK1 over JAK2 and >100-fold over JAK3 and TYK2.
In vitro activity:
Recent evidence shows that host macrophages are the major producers of IL-6 after CAR T-cell treatment. Therefore, whether itacitinib would prevent IL-6 production by host macrophages was investigated. First, murine bone marrow–derived macrophages were expanded in vitro with granulocyte-colony stimulating factor, and itacitinib was added to the cultures at day 6. LPS was added to the culture at day 7 to activate the macrophages. Prophylactic treatment with itacitinib reduced IL-6 production in a dose-dependent manner, indicating that the activity of itacitinib in reducing production of inflammatory cytokines is not exclusive to T-cells (Fig. 2A). A non-significant trend towards reduction on several other cytokines (i.e. IL-10, IL-12p70, KC/GRO, Supplementary Fig. S2) was observed.
Reference: Clin Cancer Res. 2020 Dec 1;26(23):6299-6309. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/32998963/
In vivo activity:
To study the effect of itacitinib, animals were prophylactically dosed with 60 or 120 mg/kg of itacitinib to achieve JAK1 inhibition coverage equivalent to that observed in clinical trials (27–29). When compared with vehicle-dosed animals, itacitinib was able to significantly reduce serum levels of many of the cytokines implicated in CRS (i.e., IL-6, IL-12, and IFN-γ) in a dose-dependent manner (Fig. 1A). As expected, itacitinib did not have a significant effect on cytokines independent of the JAK1 pathway (i.e., IL-5, Fig. 1A). However, not all JAK-mediated cytokines were significantly decreased (i.e. IL-4, Fig 1A). Additionally, itacitinib was also able to dose-dependently reduce CRS-implicated cytokines in a therapeutic mode, where animals were dosed with itacitinib 30 minutes after ConA challenge (Fig. 1B). To confirm the capacity of itacitinib to reduce hyperinflammation, naïve animals were challenged with anti-CD3 to induce nonspecific T-cell activation and cytokine response. Once again, corresponding animals were either prophylactically or therapeutically dosed with 120 mg/kg of itacitinib. Compared with vehicle-treated mice, itacitinib was able to significantly reduce serum levels of many of the cytokines implicated in CRS, but have no effect on cytokines independent of the JAK1 pathway (Supplementary Fig. S1A).
Reference: Clin Cancer Res. 2020 Dec 1;26(23):6299-6309. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/32998963/
|
Solvent |
mg/mL |
mM |
comments |
| Solubility |
| DMSO |
30.0 |
54.20 |
|
| Ethanol |
30.0 |
54.20 |
|
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.
Preparing Stock Solutions
The following data is based on the
product
molecular weight
553.51
Batch specific molecular weights may vary
from batch to batch
due to the degree of hydration, which will
affect the solvent
volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass |
1 mg |
5 mg |
10 mg |
| 1 mM |
1.15 mL |
5.76 mL |
11.51 mL |
| 5 mM |
0.23 mL |
1.15 mL |
2.3 mL |
| 10 mM |
0.12 mL |
0.58 mL |
1.15 mL |
| 50 mM |
0.02 mL |
0.12 mL |
0.23 mL |
In vitro protocol:
1. Huarte E, O'Connor RS, Peel MT, Nunez-Cruz S, Leferovich J, Juvekar A, Yang YO, Truong L, Huang T, Naim A, Milone MC, Smith PA. Itacitinib (INCB039110), a JAK1 Inhibitor, Reduces Cytokines Associated with Cytokine Release Syndrome Induced by CAR T-cell Therapy. Clin Cancer Res. 2020 Dec 1;26(23):6299-6309. doi: 10.1158/1078-0432.CCR-20-1739. Epub 2020 Sep 30. PMID: 32998963; PMCID: PMC7895329.
2. Covington M, He X, Scuron M, Li J, Collins R, Juvekar A, Shin N, Favata M, Gallagher K, Sarah S, Xue CB, Peel M, Burke K, Oliver J, Fay B, Yao W, Huang T, Scherle P, Diamond S, Newton R, Zhang Y, Smith P. Preclinical characterization of itacitinib (INCB039110), a novel selective inhibitor of JAK1, for the treatment of inflammatory diseases. Eur J Pharmacol. 2020 Oct 15;885:173505. doi: 10.1016/j.ejphar.2020.173505. Epub 2020 Aug 28. PMID: 32861662.
In vivo protocol:
1. Huarte E, O'Connor RS, Peel MT, Nunez-Cruz S, Leferovich J, Juvekar A, Yang YO, Truong L, Huang T, Naim A, Milone MC, Smith PA. Itacitinib (INCB039110), a JAK1 Inhibitor, Reduces Cytokines Associated with Cytokine Release Syndrome Induced by CAR T-cell Therapy. Clin Cancer Res. 2020 Dec 1;26(23):6299-6309. doi: 10.1158/1078-0432.CCR-20-1739. Epub 2020 Sep 30. PMID: 32998963; PMCID: PMC7895329.
2. Covington M, He X, Scuron M, Li J, Collins R, Juvekar A, Shin N, Favata M, Gallagher K, Sarah S, Xue CB, Peel M, Burke K, Oliver J, Fay B, Yao W, Huang T, Scherle P, Diamond S, Newton R, Zhang Y, Smith P. Preclinical characterization of itacitinib (INCB039110), a novel selective inhibitor of JAK1, for the treatment of inflammatory diseases. Eur J Pharmacol. 2020 Oct 15;885:173505. doi: 10.1016/j.ejphar.2020.173505. Epub 2020 Aug 28. PMID: 32861662.
1: Yiu ZZ, Warren RB. Novel Oral Therapies for Psoriasis and Psoriatic Arthritis. Am J Clin Dermatol. 2016 Jun;17(3):191-200. doi: 10.1007/s40257-016-0179-3. PubMed PMID: 26923915.
2: Bissonnette R, Luchi M, Fidelus-Gort R, Jackson S, Zhang H, Flores R, Newton R, Scherle P, Yeleswaram S, Chen X, Menter A. A randomized, double-blind, placebo-controlled, dose-escalation study of the safety and efficacy of INCB039110, an oral janus kinase 1 inhibitor, in patients with stable, chronic plaque psoriasis. J Dermatolog Treat. 2016 Jan 14:1-7. [Epub ahead of print] PubMed PMID: 26769332.
3: Zhang Y, Warren MS, Zhang X, Diamond S, Williams B, Punwani N, Huang J, Huang Y, Yeleswaram S. Impact on creatinine renal clearance by the interplay of multiple renal transporters: a case study with INCB039110. Drug Metab Dispos. 2015 Apr;43(4):485-9. doi: 10.1124/dmd.114.060673. Epub 2015 Jan 20. PubMed PMID: 25605813.
4: Rosenthal A, Mesa RA. Janus kinase inhibitors for the treatment of myeloproliferative neoplasms. Expert Opin Pharmacother. 2014 Jun;15(9):1265-76. doi: 10.1517/14656566.2014.913024. Epub 2014 Apr 25. Review. PubMed PMID: 24766055.
5. Liu, Pingli; Wang, Dengjin; Wu, Yongzhong; Cao, Ganfeng; Xia, Michael. A process for the preparation of key intermediates towards the synthesis of fluorotrifluoromethylisonicotinoylpiperidinylpyrrolopyrimidinylpyrazolylazetidinylacetonitrile for use as a JAK inhibitor. U.S. Pat. Appl. Publ. (2014), US 20140256941 A1 20140911.
