Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms
Open accessAbstract
Constitutive JAK2 activation in hematopoietic cells by the JAK2V617F mutation recapitulates myeloproliferative neoplasm (MPN) phenotypes in mice, establishing JAK2 inhibition as a potential therapeutic strategy. Although most polycythemia vera patients carry the JAK2V617F mutation, half of those with essential thrombocythemia or primary myelofibrosis do not, suggesting alternative mechanisms for constitutive JAK-STAT signaling in MPNs. Most patients with primary myelofibrosis have elevated levels of JAK-dependent proinflammatory cytokines (eg, interleukin-6) consistent with our observation of JAK1 hyperactivation. Accordingly, we evaluated the effectiveness of selective JAK1/2 inhibition in experimental models relevant to MPNs and report on the effects of INCB018424, the first potent, selective, oral JAK1/JAK2 inhibitor to enter the clinic. INCB018424 inhibited interleukin-6 signaling (50% inhibitory concentration [IC50] = 281nM), and proliferation of JAK2V617F+ Ba/F3 cells (IC50 = 127nM). In primary cultures, INCB018424 preferentially suppressed erythroid progenitor colony formation from JAK2V617F+ polycythemia vera patients (IC50 = 67nM) versus healthy donors (IC50 > 400nM). 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. Preliminary clinical results support these preclinical data and establish INCB018424 as a promising oral agent for the treatment of MPNs.
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Previous treatment planning was based on preclinical data and empirical results from clinical trials.
“Notably, previous treatment planning was based on preclinical data and empirical results from clinical trials (Quintas-Cardama et al., 2010; Shi et al., 2011).”
From Model Based Targeting of IL-6-Induced Inflammatory Responses in Cultured Primary Hepatocytes to Improve Application of the JAK Inhibitor Ruxolitinib (2017) · cites this paper as Quintas-Cardama et al., 2010
The Results describe using preclinical whole-blood assay findings to guide dose selection in mouse studies, and the Abstract says preliminary clinical results supported the preclinical findings. Neither passage establishes that previous treatment planning was based on both preclinical data and empirical clinical-trial results. (LLM, conf=0.78)
Experimental — accuracy not yet measuredRuxolitinib negatively influences JAK1-dependent reactions, specifically the generation of pJAK1_gp130 and pJAK1_pgp130.
“The JAK inhibitor Ruxolitinib (Lin et al., 2009; Quintas-Cardama et al., 2010) negatively influences JAK1-dependent reactions in the model, specifically the generation of pJAK1_gp130 and pJAK1_pgp130.”
From Model Based Targeting of IL-6-Induced Inflammatory Responses in Cultured Primary Hepatocytes to Improve Application of the JAK Inhibitor Ruxolitinib (2017) · cites this paper as Quintas-Cardama et al., 2010
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“The JAK inhibitor Ruxolitinib (Lin et al., 2009; Quintas-Cardama et al., 2010) negatively influences JAK1-dependent reactions in the model, specifically the generation of pJAK1_gp130 and pJAK1_pgp130.”
BackgroundMethod
- Authors
- Quintás-Cardama, A., Vaddi, K., Liu, P., Manshouri, T., Li, J., Scherle, P. A., Caulder, E., Wen, X., Li, Y., Waeltz, P., Rupar, M., Burn, T., Lo, Y., Kelley, J., Covington, M., Shepard, S., Rodgers, J. D., Haley, P., Kantarjian, H., Fridman, J. S., & Verstovsek, S.
- Affiliations
- Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston; and
- Incyte (United States) (US)
- The University of Texas MD Anderson Cancer Center (US)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2010-04-15
- Volume
- 115
- Issue
- 15
- Pages
- 3109-3117
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC3953826
- OpenAlex
- W2079645940
- Cited by
- 843
- References
- 1
- Citations by year
- 2026: 38 · 2025: 53 · 2024: 60 · 2023: 47 · 2022: 64 · 2021: 52 · 2020: 59 · 2019: 35 · 2018: 54 · 2017: 41 · 2016: 44 · 2015: 64 · 2014: 48 · 2013: 72 · 2012: 63
- FWCI
- 27.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Joe W. and Dorothy Dorsett Brown Foundation
- Incyte
- Topics
- Health Sciences › Medicine › Genetics › Myeloproliferative Neoplasms: Diagnosis and Treatment
- Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- JAK1/2 inhibitor, myeloproliferative neoplasms, JAK2 V617F mutation, polycythemia vera, primary myelofibrosis, essential thrombocythemia, IL-6 signaling, splenomegaly, oral JAK inhibitor, Ba/F3 cells, inflammatory cytokines
- MeSH terms
- Animals, Blood Cell Count, Cell Survival, Colony-Forming Units Assay, Disease Models, Animal, Drug Screening Assays, Antitumor, Hematopoietic Stem Cells, Humans, Myeloproliferative Disorders, Nitriles, Pyrazoles, Pyrimidines, Spleen, Signal Transduction, Cytokines, Treatment Outcome, Apoptosis, Amino Acid Substitution, Protein Kinase Inhibitors, Cell Proliferation, Mice, Janus Kinases, Janus Kinase 1, Janus Kinase 2
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