Ruxolitinib phosphate

Ruxolitinib phosphate is a potent JAK1/2 inhibitor with IC50s of 3.3 nM/2.8 nM, respectively, showing more than 130-fold selectivity over JAK3.

Signaling Pathways >> Autophagy >> Autophagy

Signaling Pathways >> Epigenetics >> JAK

Signaling Pathways >> JAK/STAT Signaling >> JAK

Signaling Pathways >> Stem Cell/Wnt >> JAK

Signaling Pathways >> Autophagy >> Mitophagy

Research Areas >> Cancer

JAK2:2.8 nM (IC50)

JAK1:3.3 nM (IC50)

Tyk2:19 nM (IC50)

JAK3:428 nM (IC50)

Ruxolitinib (INCB018424) potently and selectively inhibits JAK2V617F-mediated signaling and proliferation. Ruxolitinib inhibits the growth of HEL cells with EC50 of 186 nM. Ruxolitinib markedly increases apoptosis in Ba/F3-EpoR-JAK2V617F cell system, and inhibits hematopoietic progenitor cell proliferation in primary MPN patient samples[1].

Ruxolitinib (180 mg/kg, p.o.) reduces the tumor burden of mice inoculated with JAK2V617F-expressing cells without causing anemia or lymphopenia[1].

Cells are 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 is measured by cellular ATP determination using the Cell-Titer Glo luciferase reagent or viable cell counting. Values are transformed to percent inhibition relative to vehicle control, and IC50 curves are fitted according to nonlinear regression analysis of the data using PRISM GraphPad.

Mice are fed standard rodent chow and provided with water ad libitum. Ba/F3-JAK2V617F cells (105 per mouse) are inoculated intravenously into 6- to 8-week-old female BALB/c mice. Survival is monitored daily, and moribund mice are humanely killed and considered deceased at time of death. Treatment with vehicle (5% dimethyl acetamide, 0.5% methocellulose) or Ruxolitinib (INCB018424) begins within 24 hours of cell inoculation, twice daily by oral gavage. Hematologic parameters are measured using a Bayer Advia120 analyzed, and statistical significance is determined using Dunnett testing.

[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]. Fleischman AG, et al. The CSF3R T618I mutation causes a lethal neutrophilic neoplasia in mice that is responsive to therapeutic JAK inhibition. Blood. 2013 Nov 21;122(22):3628-31.

[3]. de Bock CE, et al. HOXA9 Cooperates with Activated JAK/STAT Signaling to Drive Leukemia Development. Cancer Discov. 2018 May;8(5):616-631.

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