Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms.

Blood
Alfonso Quintás-CardamaSrdan Verstovsek

Abstract

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 [IC(50)] = 281nM), and proliferation of JAK2V617F(+) Ba/F3 cells (IC(50) = 127nM). In primary cultures, INCB018424 preferentially suppressed erythroid progenitor colony formation from JAK2V617F(+) polycythemia vera patients (IC(50) = 67nM) versus healthy donors (IC(50) > 400nM). In a mouse model of JAK2V617F(+) MPN, o...Continue Reading

References

May 1, 1977·The Journal of Clinical Investigation·E D ZanjaniL R Wasserman
Jun 13, 1974·The New England Journal of Medicine·R Gabriel
Jun 13, 1974·The New England Journal of Medicine·J F Prchal, A A Axelrad
Nov 3, 1995·Science·T NosakaJ N Ihle
Apr 25, 2000·Molecular and Cellular Biology·P SaharinenO Silvennoinen
Apr 27, 2000·The New England Journal of Medicine·A Tefferi
Mar 23, 2005·Lancet·E Joanna BaxterUNKNOWN Cancer Genome Project
Apr 29, 2005·The New England Journal of Medicine·Robert KralovicsRadek C Skoda
May 3, 2005·The Journal of Biological Chemistry·Runxiang ZhaoZhizhuang Joe Zhao
Jul 1, 2005·Journal of Cellular Biochemistry·Huei-Mei HuangTing-Wei Chang
Aug 24, 2005·British Journal of Haematology·Katerina E PanteliKonstantinos L Bourantas
Dec 21, 2005·Proceedings of the National Academy of Sciences of the United States of America·Xiaohui LuHarvey Lodish
Apr 11, 2006·Proceedings of the National Academy of Sciences of the United States of America·Catriona H M JamiesonIrving L Weissman
May 3, 2006·Proceedings of the National Academy of Sciences of the United States of America·Hans-Guido WendelScott W Lowe
Dec 22, 2006·PloS One·Virginia M ZaleskasRichard A Van Etten
Nov 16, 2007·Proceedings of the National Academy of Sciences of the United States of America·Anuradha PradhanGary W Reuther
Jul 11, 2008·Immunological Reviews·Marko PesuJohn J O'Shea
Aug 7, 2008·Seminars in Cell & Developmental Biology·William VainchenkerStefan N Constantinescu

❮ Previous
Next ❯

Citations

Dec 4, 2010·Investigational New Drugs·Sridurga MithraprabhuAndrew Spencer
Apr 29, 2010·Current Hematologic Malignancy Reports·Malcolm A Smith
Oct 5, 2013·Current Hematologic Malignancy Reports·Moosa Qureshi, Claire Harrison
Oct 23, 2013·Current Hematologic Malignancy Reports·Niccolò BartalucciAlessandro M Vannucchi
Sep 3, 2010·Current Oncology Reports·Emma ScottMartin Carroll
May 15, 2013·International Journal of Hematology·Neha BhagwatPriya Koppikar
Oct 2, 2012·Molecular Diagnosis & Therapy·Raoul TibesRuben A Mesa
Jul 23, 2013·European Journal of Medicinal Chemistry·Jun LiangSteven Magnuson
Nov 24, 2004·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Hai-Xia Zhang, Man-Cang Liu
Mar 26, 1998·Biochimica Et Biophysica Acta·T IizukaT Watanabe
Sep 6, 2002·Biochimica Et Biophysica Acta·Ronald F CoburnShamshad Cockcroft
Nov 18, 2011·Journal of Medicinal Chemistry·Laurie B SchenkelStephanie Geuns-Meyer
May 18, 2012·Journal of Medicinal Chemistry·Janusz J KulagowskiMark Zak
Oct 16, 2012·Journal of Medicinal Chemistry·Emily J HananJoseph P Lyssikatos
Aug 15, 2013·Journal of Medicinal Chemistry·Oscar P J van LindenChris de Graaf
Apr 24, 2013·Molecular Therapy : the Journal of the American Society of Gene Therapy·Tim HeinrichSebastian Newrzela
Feb 2, 2011·Nature Reviews. Drug Discovery·Alfonso Quintás-CardamaSrdan Verstovsek
Feb 2, 2012·Nature Reviews. Drug Discovery·Ruben A MesaPeter Kirkpatrick
Aug 2, 2013·Nature Reviews. Drug Discovery·Gabriella MiklossyJames Turkson
Sep 17, 2010·The New England Journal of Medicine·Srdan VerstovsekAyalew Tefferi
Mar 2, 2012·The New England Journal of Medicine·Claire HarrisonGiovanni Barosi
Mar 2, 2012·The New England Journal of Medicine·Srdan VerstovsekHagop M Kantarjian
May 10, 2013·The New England Journal of Medicine·Julia E MaxsonJeffrey W Tyner
Jan 10, 2012·Current Opinion in Hematology·Francesco PassamontiDomenica Caramazza
Jul 11, 2013·Current Opinion in Pediatrics·Martha-Estrella García-PérezPatrice E Poubelle
Jul 7, 2012·Blood·Nikolaos PapadantonakisKatya Ravid
Nov 21, 2013·Molecular Cancer·Miguel GallardoJoaquin Martinez-Lopez
Nov 29, 2013·Journal of Hematology & Oncology·Ruben A Mesa, Jorge Cortes
Nov 29, 2013·Journal of Hematology & Oncology·Moshe TalpazSrdan Verstovsek
Feb 23, 2012·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Pasquale Sansone, Jacqueline Bromberg
Feb 6, 2013·PloS One·Costanza BoganiUNKNOWN Associazione Italiana per la Ricerca sul Cancro AGIMM Gruppo Italiano Malattie Mieloproliferative

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.