Many Metabolic Disorders Have Been Associated With Aberrations

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

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