R723, a selective JAK2 inhibitor, effectively treats JAK2V617F-induced murine myeloproliferative neoplasm

Abstract

The activating mutations in JAK2 (including JAK2V617F) that have been described in patients with myeloproliferative neoplasms (MPNs) are linked directly to MPN pathogenesis. We developed R723, an orally bioavailable small molecule that inhibits JAK2 activity in vitro by 50% at a concentration of 2nM, while having minimal effects on JAK3, TYK2, and JAK1 activity. R723 inhibited cytokineindependent CFU-E growth and constitutive activation of STAT5 in primary hematopoietic cells expressing JAK2V617F. In an anemia mouse model induced by phenylhydrazine, R723 inhibited erythropoiesis. In a leukemia mouse model using Ba/F3 cells expressing JAK2V617F, R723 treatment prolonged survival and decreased tumor burden. In V617F-transgenic mice that closely mimic human primary myelofibrosis, R723 treatment improved survival, hepatosplenomegaly, leukocytosis, and thrombocytosis. R723 preferentially targeted the JAK2-dependent pathway rather than the JAK1-and JAK3-dependent pathways in vivo, and its effects on T and B lymphocytes were mild compared with its effects on myeloid cells. Our preclinical data indicate that R723 has a favorable safety profile and the potential to become an efficacious treatment for patients with JAK2V617F-positive MPNs. (Blood. 2011;117(25):6866-6875)

JAK2V617F expression in mice amplifies early hematopoietic cells and gives them a competitive advantage that is hampered by IFNα

“…43 These drugs have essentially demonstrated palliative virtues with limited effects on the selective reduction of JAK2 V617F -positive cells in human as in mice. 11,44 In contrast, IFNa treatment has demonstrated hematological and molecular responses, including complete molecular responses in PV patients. 22 Therefore, we tested the efficacy of IFNa in competitive transplantation models that included normal hematopoiesis and 2 different levels of JAK2 V617F disease burden.…”

JAK inhibitors for myeloproliferative neoplasms: clarifying facts from myths

“…Specific targeting of JAK2V617F, if it were possible, might spare patients the untoward effects of wild-type JAK1 (cytokine rebound syndrome) or JAK2 (myelosuppression) inhibition, but therapeutic outcome might be limited to suppression of a subclone with a subordinate role in disease phenotype or clonal evolution (Figure 1), 68 Current "JAK2-selective" drugs do not meaningfully distinguish between wild-type JAK2 and JAK2V617F, 69 and are therefore subjected to consequences of wild-type JAK2 inhibition, which includes induction or worsening of anemia. 59 Off-target activity outside the JAK family of kinases might explain the occurrence of certain side effects; for example, gastrointestinal disturbances are commonly seen with drugs that concomitantly inhibit FLT3 (eg, lestaurtinib, SAR302503, or SB1518).…”

Selective JAK1 inhibitor and selective Tyk2 inhibitor patents

“…GLPG-0634 has been reported to have IC 50 values of 10, 28, 810 and 116 nM against the four kinase of the JAK family and to show much greater JAK1 selectivity in whole blood assays [47]. However, this presentation did highlight the key role of the cyclopropylamide group present in (15). GLPG-0634 has shown clear evidence of efficacy in Phase II studies [48].…”

“…This has led to diverse chemotypes being identified as providing selectivity for these kinases. JAK2 selective inhibitors have been identified by Rigel (R-723) [15], Ambit (AC-430) [16,17], Cephalon (CEP-33779) [18], Bristol-Myers Squibb (BMS-911543) [19] and Amgen (1) [20] (Figure 1), whereas JAK3 selective inhibitors have been identified by Novartis (2) [21], Roche (3) [22] and Vertex (VX-509) ( Figure 2). VX-509 has progressed to Phase II studies in rheumatoid arthritis and has been reported to show < 10-fold selectivity for JAK3 at the kinase level but considerably better selectivity in cellular assays [23].…”