The Recent Medicinal Chemistry Development of Jak2 Tyrosine Kinase Small Molecule Inhibitors

R.      Baskin; A.      Majumder; P.      P. Sayeski

doi:10.2174/092986710794182953

Abstract

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.

Keywords: JAK2, small molecule inhibitors, medicinal chemistry, structure activity relationships, Jak2-V617F mutation, myeloproliferative neoplasms (MPNs), structure activity relationship (SAR), cytokines, tyrphostin AG490, pyrazines, pyrimidines, azaindoles, aminoindazoles, deazapurines, stilbenes, benzoxazoles, quinoxalines, trifluoromethyl groups, phenolic hydroxide, pyrazolo nicotinonitrile, 5-bromoaminoindazole, 4-tert-butyl sulfonamide, G6, hydroxyls, fluorine, electronegativity