INCB18424 (Ruxolitinib), the most advanced JAK-1 and JAK-2 inhibitor, is in Phase III testing to treat myelofibrosis. INCB18424 demonstrated potent in vitro cellular activity (100-130 nM) in an engineered Ba/F3 cell line harboring the JAK2V617F mutation and EPO-independent erythroid colony growth of precursor cells from PV patients (IC50 of 67 nM) while showing lesser effect on normal colony formation from healthy donors (IC50 > 400 nM).
|Cell lines||Ba/F3-EpoR-JAK2V617F and HEL cell lines|
|Preparation method||Cell proliferation assay. 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 (Promega) 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.|
|Concentrations||0~10 µ M|
|Incubation time||48 h|
|Animal models||myeloproliferative neoplasm mouse model|
|Formulation||5% dimethyl acetamide, 0.5% methocellulose|
|Dosages||180mg/kg began within 24 hours of cell inoculation, twice daily|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Source||Leukemia (2013). Figure 2. INCB18424|
|Cell Lines||leukemia cells|
|Incubation Time||48 h|
|Results||INCB18424 showed a significantly better inhibitory effect than TG101209 at concentrations below 1 μM. Both inhibitors also promoted apoptosis (Figure 2b) and delayed cell cycle progression (Figure 2c) of the AEtr leukemia cell line.|
|Source||Leukemia (2013). Figure 1. INCB18424|
|Cell Lines||AML1–ETO- and AE9a-transformed cells|
|Concentrations||150, 300, 600, 1200 nM|
|Incubation Time||36 h|
|Results||Similar to the shRNA results, both inhibitors reduced the colony-forming ability of the transformed cells in a dose-dependent manner|
Ruxolitinib as potential targeted therapy for patients with JAK2 rearrangements.
Chase A, et al. Haematologica. 2012 Aug 8. PMID: 22875628.
Biology and Clinical Management of Myeloproliferative Neoplasms and Development of the JAK Inhibitor Ruxolitinib.
Mascarenhas J, et al. Curr Med Chem. 2012 Jul 24. PMID: 22830345.
Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemia.
Eghtedar A, et al. Blood. 2012 May 17;119(20):4614-8. PMID: 22422826.
JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis.
Harrison C, et al. N Engl J Med. 2012 Mar 1;366(9):787-98. PMID: 22375970.
|Related JAK Products|
PF-06651600 is a potent and irreversible JAK3-selective inhibitor with an IC50 of 33.1 nM but without activity (IC50 > 10 000 nM) against JAK1, JAK2, and TYK2.
Upadacitinib (ABT-494) is a potent and selective Janus kinase (JAK) 1 inhibitor being developed for the treatment of several autoimmune disorders with an IC50 of 43 nM.
Ruxolitinib phosphate(INCB018424 phosphate) is the first potent, selective, JAK1/2 inhibitor to enter the clinic with IC50 of 3.3 nM/2.8 nM, >130-fold selectivity for JAK1/2 versus JAK3.
Oclacitinib is a novel inhibitor of JAK family members with IC50 ranging from 10 to 99 nM and JAK1-dependent cytokines with IC50 ranging from 36 to 249 nM, which did not inhibit a panel of 38 non-JAK kinases.
Baricitinib phosphate(INCB 028050; LY 3009104) is a selective JAK1 and JAK2 inhibitor with IC50 of 5.9 nM and 5.7 nM, ~70 and ~10-fold selective versus JAK3 and Tyk2, no inhibition to c-Met and Chk2.
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