The recent medicinal chemistry development of Jak2 tyrosine kinase small molecule inhibitors.
Since the discovery of the Jak2-V617F mutation as the causative agent in a large number of myeloproliferative neoplasms (MPNs), there has been a drive to develop Jak2 specific inhibitors that can be used in therapy for MPN patients and other Jak2-related pathologies. Over the past few years, a number of research groups have sought to develop Jak2 tyrosine kinase inhibitors. These compounds are currently in pre-clinical or clinical trials. Unfortunately, there is still a need for more potent, specific, and orally bioavailable drugs to treat these diseases. Within the past twelve months, a variety of medicinal chemistry techniques have produced several lead compounds that exhibit promising Jak2 inhibitory properties. The majority of these inhibitors target the Jak2 kinase domain in general and the ATP-binding pocket in particular. In this review, we summarize these studies and discuss the structure activity relationship (SAR) properties of several compounds. As we learn more about the key structural components that provide potency and specificity in Jak2 inhibition, we will come closer to finding suitable treatment options for individuals suffering from Jak2-mediated pathologies.
Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL 32610, USA.
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Baskin
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Majumder
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Sayeski
D002626:Chemistry, Pharmaceutical; D015195:Drug Design; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D008970:Molecular Weight; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D047428:Protein Kinase Inhibitors; C507924:JAK2 protein, human; D053614:Janus Kinase 2