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INCB18424 – JACKING THE JAK2

Introduction: JAK2 in relation to metabolic blood disorders

The transmission of signals from extracellular factors through the cell membrane to effect actions within the cell cytosole and nucleus is conducted along pathways of protein to protein interactions. Many metabolic disorders have been associated with aberrations in these pathways causing a variety of destructive cellular actions. Many of these diseases possess no known cure and in response research has focused on the mechanisms behind the progression of these diseases. One area that has received a lot of attention is the possibility that the natural immune function can be detrimental to healthy growth patterns if over stimulated by mutations in the genetic information of individuals. A key series of proteins in the immune response is the Janus kinases (JAK), a series of four distinct but domain related kinases located in the cellular cytosole. These kinases form a distinct link between extracellular immune function ligands and a direct regulation of transcription of genetic information. However, a mutation of the JAK2 isoform has been associated with degenerative effects such as myeloproliferative neoplasms, thrombocythemia, polycythemia vera and psoriasis [1]. The mutation of JAK2, known as V617F, has been detected in a variety of conditions that tend not to have any other mutational triggers such negative Philadelphia chromosome or KRAS mutations [2-8] Specific inhibition of the Janus pathway proteins has led to some significant results in arthritis and psoriasis with such molecules as CP690550, TG101348, XL019 and CEP-701 [9-12].

A small molecule receiving significant attention is the relatively new product under development called INCB18424. This molecule has been shown to be particularly effective in the myeloproferative disorders; and has rapidly progressed from preclinical investigations up to and including phase III trials status.

INCB18424: Properties and Availability

INCB18424 is a small molecule developed by Incyte pharmaceuticals and Novartis under the formulation trade names Jakafi, Incyte and Ruxolitinib. This small molecule has been demonstrated to inhibit the JAK pathway including the specific V617F mutation with a sensitivity (INCB18424 IC50) towards JAK1&2 (3.5  ± 1 nM) [13;14]. INCB18424 structure consists of pyrimidine core molecule with a pyrazol linked propane nitrile substitution which leads to a poor solubility in aqueous solutions, typical for structures of this type. The INCB81424 solubility in ethanol is unknown but solutions can be made in DMSO although saturation specifications are not given. Several INCB18424 suppliers are available for this product giving similar research quality material for a price range of $87 - $250 for 10 mg free base. To increase solubility of this product for oral formulations the phosphate salt is available at a slightly higher price but is much harder to obtain.

INCB18424: Preclinical and Clinical Investigations

As recently as 2009 the small molecule INCB18424 was synthesized which demonstrate a selective inhibition of the JAK 1 and JAK 2 kinases [15]. Investigations with compound focused on the initial screening results for activity against myeloproliferative disorders where significant efficacy was observed [16-18]. Pharmacokinetics demonstrated a nearly 95% absorption for this molecule from oral formulations which is usual for this type of structure [19]. INCB18424 clinical trials were initiated quickly since no known treatment profiles exists for certain myeloproliferative disorders revealing clear and extended responses to this drug [20]. The clinical benefits of INCB18424 were recognized when in 2011 it received approval for first line use in myeloproliferative disorders [21] However, the INCB81424 JAK inhibitor has demonstrated some toxicity in a proportion of patients which has led to the discontinuation of treatment. This has revealed that this molecule has significant withdrawl symptoms associated with it and serious attention should be given to the tapered discontinuation of this drug [22]

References

    1.    Shetty S, Kulkarni B et al. JAK2 mutations across a spectrum of venous thrombosis cases. Am J Clin Pathol 2010; 134(1):82-85.

    2.    Pich A, Riera L et al. JAK2V617F activating mutation is associated with the myeloproliferative type of chronic myelomonocytic leukaemia. J Clin Pathol 2009; 62(9):798-801.

    3.    Silva RR, Domingues Hatzlhofer BL et al. JAK2 V617F Mutation Prevalence in Myeloproliferative Neoplasms in Pernambuco, Brazil. Genet Test Mol Biomarkers 2012.

    4.    Weinberg I, Borohovitz A et al. Janus Kinase V617F mutation in cigarette smokers. Am J Hematol 2012; 87(1):5-8.

    5.    Sokolowska B, Nowaczynska A et al. JAK2 mutation status, hemostatic risk factors and thrombophilic factors in essential thrombocythemia (ET) patients. Folia Histochem Cytobiol 2011; 49(2):267-271.

    6.    Yoo EH, Jang JH et al. Prevalence of overt myeloproliferative neoplasms and JAK2 V617F mutation in Korean patients with splanchnic vein thrombosis. Int J Lab Hematol 2011; 33(5):471-476.

    7.    Sharma A, Buxi G et al. JAK2-positive Philadelphia-negative myeloproliferative neoplasms. Indian J Pathol Microbiol 2011; 54(1):117-120.

    8.    Nielsen C, Birgens HS et al. The JAK2 V617F somatic mutation, mortality and cancer risk in the general population. Haematologica 2011; 96(3):450-453.

    9.    Verstovsek S. Therapeutic potential of JAK2 inhibitors. Hematology Am Soc Hematol Educ Program 2009;636-642.

  10.    Tasocitinib. Drugs R D 2010; 10(4):271-284.

  11.    West K. CP-690550, a JAK3 inhibitor as an immunosuppressant for the treatment of rheumatoid arthritis, transplant rejection, psoriasis and other immune-mediated disorders. Curr Opin Investig Drugs 2009; 10(5):491-504.

  12.    Fridman JS, Scherle PA et al. Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050. J Immunol 2010; 184(9):5298-5307.

  13.    Punwani N, Scherle P et al. Preliminary clinical activity of a topical JAK1/2 inhibitor in the treatment of psoriasis. J Am Acad Dermatol 2012.

  14.    Ostojic A, Vrhovac R et al. Ruxolitinib: a new JAK1/2 inhibitor that offers promising options for treatment of myelofibrosis. Future Oncol 2011; 7(9):1035-1043.

  15.    Lin Q, Meloni D et al. Enantioselective synthesis of Janus kinase inhibitor INCB018424 via an organocatalytic aza-Michael reaction. Org Lett 2009; 11(9):1999-2002.

  16.    Barosi G, Rosti V. Novel strategies for patients with chronic myeloproliferative disorders. Curr Opin Hematol 2009; 16(2):129-134.

  17.    Arellano-Rodrigo E, Alvarez-Larran A. JAK inhibition in myelofibrosis. N Engl J Med 2010; 363(25):2464-2465.

  18.    Quintas-Cardama A, Vaddi K 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.

  19.    Shilling AD, Nedza FM et al. Metabolism, excretion, and pharmacokinetics of [14C]INCB018424, a selective Janus tyrosine kinase 1/2 inhibitor, in humans. Drug Metab Dispos 2010; 38(11):2023-2031.

  20.    Verstovsek S, Kantarjian H et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med 2010; 363(12):1117-1127.

  21.    Mesa RA, Yasothan U et al. Ruxolitinib. Nat Rev Drug Discov 2012; 11(2):103-104.

  22.    Tefferi A, Pardanani A. Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis. Mayo Clin Proc 2011; 86(12):1188-1191.

 

Related Products

Cat.No. Product Name Information Publications Customer Product Validation
S2736 Fedratinib (TG101348) Fedratinib (SAR302503, TG101348) is a selective inhibitor of JAK2 with IC50 of 3 nM in cell-free assays, 35- and 334-fold more selective for JAK2 versus JAK1 and JAK3. Fedratinib also inhibits FMS-like tyrosine kinase 3 (FLT3) and RET (c-RET) with IC50 of 15 nM and 48 nM, respectively. Fedratinib has potential antineoplastic activity. Fedratinib inhibits proliferation and induces apoptosis. Phase 2. (59) (4)

Related Targets

JAK