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Janus Kinases (JAK) Inhibitors for the Treatment of Myeloproliferative Disorders

By Drug Discovery Trends Editor | June 3, 2011

The Janus kinases are made up of a family of four cytoplasmic tyrosine kinases—JAK1, JAK2, JAK3, and TYK2—that play pivotal roles in the signaling pathways of many cytokines, hormones, and growth factors. These signaling pathways regulate important physiological processes such as immune response to pathogens, erythropoiesis, and thrombopoiesis. Aberrant signaling of the JAK kinases are thought to lead to numerous diseases, including hematological malignancies, allergies, asthma, and rheumatoid arthritis. The inhibition of JAK kinases may provide a novel therapeutic modality for managing these debilitating conditions.

Myeloproliferative disorders (MPDs), such as myelofibrosis (MF), are hematopoietic disorders involving the overproduction of terminally differentiated cells. In the specific case of MF, the bone marrow is replaced with scar tissue leading to a decrease in the production of red blood cells. Subsequent enlargement of the spleen and/or liver may also occur as the organs try to replenish blood cells, which are no longer being generated in the bone marrow. Common treatments are palliative, frequently ineffective, and do not alter the natural course of MF.1 Treatments for MF are focused on patients’ symptoms and the severity of their blood count. Patients have a median survival of about five years, although some patients experience survival of longer than 10 years.2 

Currently there is no known cause for MF, although in 2005, mutations that directly or indirectly led to deregulated activation of nonreceptor tyrosine kinase (TK) Janus-activated kinase 2 (JAK2) have been implicated in the pathogenesis of MPDs.1 These mutations activate the JAK2-signal transducer and activator of transcription (STAT) intracellular signaling pathways, which lead to increased cellular proliferation and resistance to apoptosis.3 These discoveries, in the regulation of signaling pathways, have led to the development of small-molecule drugs, referred to as JAK2 inhibitors, as potential therapeutic agents for MPD.

S*BIO is developing its lead small molecule drug candidate, SB1518, a potent, selective, and orally active inhibitor of JAK2 with therapeutic potential for the treatment of MPDs. SB1518 selectively inhibits the proliferation of cell lines driven by JAK2 or its mutants by reducing basal phosphorylation of JAK2 in a concentration-dependant manner. The physicochemical, metabolic, and pharmacokinetic properties of SB1518 render it amenable to once-daily oral dosing.

S*BIO is currently completing a Phase 2 clinical trial of SB1518 in the United States and Australia in patients with symptomatic myelofibrosis and enlarged spleens. The primary goal of the trial is to evaluate spleen response rate in such patients. Interim data from the Phase 2 trials has demonstrated promising efficacy and safety results; SB1518 does not cause myelosuppression and has readily manageable gastrointestinal side effects.

Reference
1. Verstovsek S. Janus-Activated Kinase 2 Inhibitors: A New Era of Targeted Therapies Providing Significant Clinical Benefit for Philadelphia Chromosome – Negative Myeloproliferative Neoplams. JCO. 2011; 29(7):781-788.
2. Vannucchi A, Guglielmelli P. Recent advances in diagnosis and treatment of chronic myeloproliferative neoplams. [Online] February 24, 2010. https://f1000.com/reports/medicine/content/2/16.
3. Tefferi A. Novel mutations and their function and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia. 2010; 24(6):1128-1138.


Filed Under: Drug Discovery

 

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