JAK2 inhibitors for the treatment of myeloproliferative disorders Free

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The molecular pathogenesis of the myeloproliferative disorders (MPDs) polycythemia vera, essential thrombocytosis, and myelofibrosis with myeloid metaplasia has been conclusively linked to an activating mutation of JAK2 (Janus Associated Kinase 2). A G-T transversion event in exon 14 that translates into a substitution of phenylalanine for valine at amino residue 617 leads to constitutive activation of JAK2V617F in a majority of these MPD cases. Assays in several laboratories indicate that between 90-100% of patients with polycythemia vera harbor this allele. Because the JAK2V617F gain-of-function mutant affects such a large patient population, pharmacologically targeting the mutated JAK2 is highly clinically relevant. In order to address this unmet clinical need we designed and synthesized a series of structurally novel compounds for their capacity to inhibit JAK2V617F. Compounds were identified which potently inhibited JAK2 enzyme, with potencies as low as 1 nM. Subsets of this group were subsequently identified which were highly selectivity against undesirable off-target kinases, including up to 100X selectivity versus JAK3 and potently inhibiting less than 5% of the kinases evaluated in a commercially available, phylogenetically diverse panel of 75 kinases. Compounds were then advanced into in vitro assays in JAK2V617F transformed cell lines in which exemplary compounds potently inhibited JAK2-driven cell proliferation and STAT5 phosphorylation. Compounds from this series were subsequently shown to be orally available in multiple species and efficacious in rodent models of JAK2-driven disease.

Conclusion: TargeGen has synthesized a series of JAK2V617F inhibitors with promising potency, selectivity and pharmaceutical properties for utility in the treatment of myeloproliferative disorders.