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Ruxolitinib

Catalog No. T1829 CAS 941678-49-5

Synonyms: (R)-Ruxolitinib, INCB018424

Ruxolitinib is a potent and selective JAK1/2 inhibitor (IC50: 3.3/2.8 nM) and is relatively less selective for JAK3 (IC50: 322 nM).

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Ruxolitinib, CAS 941678-49-5

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Purity: 98%

Biological Description

Chemical Properties

Storage & Solubility Information

Description	Ruxolitinib is a potent and selective JAK1/2 inhibitor (IC50: 3.3/2.8 nM) and is relatively less selective for JAK3 (IC50: 322 nM).
Targets&IC50	JAK2:2.8 nM (cell free), JAK1:3.3 nM (cell free), Tyk2:19 nM (cell free)
In vitro	Ruxolitinib (INCB018424) inhibited interleukin-6 signaling (IC50: 281 nM), and proliferation of JAK2V617F(+) Ba/F3 cells (IC50: 127 nM). In primary cultures, INCB018424 preferentially suppressed erythroid progenitor colony formation from JAK2V617F(+) polycythemia vera patients (IC50: 67 nM) versus healthy donors (IC50 > 400nM) [1].
In vivo	In a mouse model of JAK2V617F(+) MPN, oral INCB018424 markedly reduced splenomegaly and circulating levels of inflammatory cytokines, and preferentially eliminated neoplastic cells, resulting in significantly prolonged survival without myelosuppressive or immunosuppressive effects [1]. A total of 28% of the patients in the ruxolitinib group had at least a 35% reduction in spleen volume at week 48, as compared with 0% in the group receiving the best available therapy; the corresponding percentages at week 24 were 32% and 0%. At 48 weeks, the mean palpable spleen length had decreased by 56% with ruxolitinib but had increased by 4% with the best available therapy [2]. The primary endpoint was reached in 41.9% of patients in the ruxolitinib group as compared with 0.7% in the placebo group. A reduction in spleen volume was maintained in patients who received ruxolitinib; 67.0% of the patients with a response had the response for 48 weeks or more. There was an improvement of 50% or more in the total symptom score at 24 weeks in 45.9% of patients who received ruxolitinib as compared with 5.3% of patients who received placebo [3].
Kinase Assay	The kinase domains of human JAK1 (837-1142), JAK2 (828-1132), JAK3 (781-1124), and Tyk2 (873-1187) were cloned by PCR with N-terminal epitope tags. Recombinant proteins were expressed using Sf21 cells and baculovirus vectors and purified with affinity chromatography. JAK kinase assays used a homogeneous time-resolved fluorescence assay with the peptide substrate (-EQEDEPEGDYFEWLE). Each enzyme reaction was carried out with test compound or control, JAK enzyme, 500nM peptide, adenosine triphosphate (ATP; 1mM), and 2.0% dimethyl sulfoxide (DMSO) for 1 hour. The 50% inhibitory concentration (IC50) was calculated as the compound concentration required for inhibition of 50% of the fluorescent signal. Biochemical assays for CHK2 and c-MET enzymes were performed using standard conditions (Michaelis constant [Km] ATP) with recombinantly expressed catalytic domains from each protein and synthetic peptide substrates. An additional panel of kinase assays (Abl, Akt1, AurA, AurB, CDC2, CDK2, CDK4, CHK2, c-kit, c-Met, EGFR, EphB4, ERK1, ERK2, FLT-1, HER2, IGF1R, IKKα, IKKβ, JAK2, JAK3, JNK1, Lck, MEK1, p38α, p70S6K, PKA, PKCα, Src, and ZAP70) was performed using standard conditions using 200nM INCB018424. Significant inhibition was defined as more than or equal to 30% (average of duplicate assays) compared with control values [1].
Cell Research	Cells were seeded at 2000/well of white bottom 96-well plates, treated with compounds from DMSO stocks (0.2% final DMSO concentration), and incubated for 48 hours at 37°C with 5% CO2. Viability was measured by cellular ATP determination using the Cell-Titer Glo luciferase reagent or viable cell counting. Values were transformed to percent inhibition relative to vehicle control, and IC50 curves were fitted according to nonlinear regression analysis of the data using PRISM GraphPad [1].
Animal Research	All of the procedures were conducted in accordance with the US Public Health Service Policy on Humane Care and Use of Laboratory Animals. Mice were fed standard rodent chow and provided with water ad libitum. Ba/F3-JAK2V617F cells (10^5 per mouse) were inoculated intravenously into 6- to 8-week-old female BALB/c mice. Survival was monitored daily, and moribund mice were humanely killed and considered deceased at time of death. Treatment with vehicle (5% dimethylacetamide, 0.5% methocellulose) or INCB018424 began within 24 hours of cell inoculation, twice daily by oral gavage. Hematologic parameters were measured using a Bayer Advia120 analyzed, and statistical significance was determined using Dunnett testing [1].

Synonyms	(R)-Ruxolitinib, INCB018424
Molecular Weight	306.37
Formula	C17H18N6
CAS No.	941678-49-5

Storage

Powder: -20°C for 3 years

In solvent: -80°C for 2 years

Solubility Information

H2O: <1 mg/mL

DMSO: 57 mg/mL (186 mM)

Ethanol: <1 mg/mL

( < 1 mg/ml refers to the product slightly soluble or insoluble )

References and Literature

1. Quintas-Cardama A, et al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood, 2010, 115(15), 3109-3117. 2. Harrison C, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012 Mar 1;366(9):787-98. 3. Verstovsek S, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med, 2012, 366(9), 799-807. 4. Datta J, Lamichhane P, Dai X, et al. Combined MEK and STAT3 inhibition reprograms the tumor microenvironment to overcome immunotherapy resistance in pancreatic cancer[J]. bioRxiv. 2021 5. Ryan M M, Patel M, Hogan K, et al. Ruxolitinib inhibits IFNγ licensing of human bone marrow derived Mesenchymal Stromal Cells[J]. Transplantation and Cellular Therapy. 2021, 27(5): 389. e1-389. e10. 6. Chen X, Gao C, Cheng Z, et al. Ruxolitinib exerts neuroprotection via repressing ferroptosis in a mouse model of traumatic brain injury[J]. Experimental Neurology. 2021: 113762. 7. Zhang C, Yan Y, He H, et al. IFN-stimulated P2Y13 protects mice from viral infection by suppressing the cAMP/EPAC1 signaling pathway[J]. Journal of molecular cell biology. 2018 Aug 22. 8. Espinet E, Gu Z, Imbusch C D, et al. Cancer Discovery. 2021, 11(3): 638-659.

Citations

1. Datta J, Dai X, Bianchi A, et al. Combined MEK and STAT3 inhibition uncovers stromal plasticity by enriching for cancer-associated fibroblasts with mesenchymal stem cell-like features to overcome immunotherapy resistance in pancreatic cancer. Gastroenterology. 2022 2. Datta J, Lamichhane P, Dai X, et al. Combined MEK and STAT3 inhibition reprograms the tumor microenvironment to overcome immunotherapy resistance in pancreatic cancer. Cancer Research. 2022, 82(12_Supplement): 4187-4187. 3. Si H, Wang J, He R, et al. Identification of U937JAK3-M511I Acute Myeloid Leukemia Cells as a Sensitive Model to JAK3 Inhibitor. Frontiers in oncology. 2021, 11: 807200-807200. 4. Alfi O, Hamdan M, Wald O, et al. SARS-CoV-2 Omicron Induces Enhanced Mucosal Interferon Response Compared to other Variants of Concern, Associated with Restricted Replication in Human Lung Tissues. Viruses. 2022, 14(7): 1583. 5. Zhang C, Yan Y, He H, et al. IFN-stimulated P2Y13 protects mice from viral infection by suppressing the cAMP/EPAC1 signaling pathway. Journal of Molecular Cell Biology. 2018 Aug 22 6. Chen X, Gao C, Cheng Z, et al. Ruxolitinib exerts neuroprotection via repressing ferroptosis in a mouse model of traumatic brain injury. Experimental Neurology. 2021: 113762.

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Keywords

Ruxolitinib 941678-49-5 Angiogenesis Apoptosis Autophagy Chromatin/Epigenetic JAK/STAT signaling Stem Cells Tyrosine Kinase/Adaptors Tyrosine Kinases Mitophagy JAK INCB 18424 (R)-Ruxolitinib inhibit Mitochondrial Autophagy INCB18424 Janus kinase INCB018424 INCB-18424 Inhibitor inhibitor

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