The high frequency of activating RAS or BRAF mutations in cancer provides strong rationale for targeting the mitogen-activated protein kinase (MAPK) pathway. Selective BRAF and MAP-ERK kinase (MEK) inhibitors have shown clinical effi cacy in patients with melanoma. However, the majority of responses are transient, and resistance is often associated with pathway reactivation of the extracellular signal-regulated kinase (ERK) signaling pathway. Here, we describe the identifi cation and characterization of SCH772984, a novel and selective inhibitor of ERK1/2 that displays behaviors of both type I and type II kinase inhibitors. SCH772984 has nanomolar cellular potency in tumor cells with mutations in BRAF , NRAS , or KRAS and induces tumor regressions in xenograft models at tolerated doses. Importantly, SCH772984 effectively inhibited MAPK signaling and cell proliferation in BRAF or MEK inhibitor-resistant models as well as in tumor cells resistant to concurrent treatment with BRAF and MEK inhibitors. These data support the clinical development of ERK inhibitors for tumors refractory to MAPK inhibitors. SIGNIFICANCE: BRAF and MEK inhibitors have activity in MAPK-dependent cancers with BRAF or RAS mutations. However, resistance is associated with pathway alterations resulting in phospho-ERK reactivation. Here, we describe a novel ERK1/2 kinase inhibitor that has antitumor activity in MAPK inhibitor-naïve and MAPK inhibitor-resistant cells containing BRAF or RAS mutations. Cancer Discov; 3(7); 742-50.

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A high percentage of patients with the myeloproliferative disorder polycythemia vera (PV) harbor a Val617→Phe activating mutation in the Janus kinase 2 (JAK2) gene, and both cell culture and mouse models have established a functional role for this mutation in the development of this disease. We describe the properties of MRLB-11055, a highly potent inhibitor of both the WT and V617F forms of JAK2, that has therapeutic efficacy in erythropoietin (EPO)-driven and JAK2V617F-driven mouse models of PV. In cultured cells, MRLB-11055 blocked proliferation and induced apoptosis in a manner consistent with JAK2 pathway inhibition. MRLB-11055 effectively prevented EPO-induced STAT5 activation in the peripheral blood of acutely dosed mice, and could prevent EPO-induced splenomegaly and erythrocytosis in chronically dosed mice. In a bone marrow reconstituted JAK2V617F-luciferase murine PV model, MRLB-11055 rapidly reduced the burden of JAK2V617F-expressing cells from both the spleen and the bone marrow. Using real-time in vivo imaging, we examined the kinetics of disease regression and resurgence, enabling the development of an intermittent dosing schedule that achieved significant reductions in both erythroid and myeloid populations with minimal impact on lymphoid cells. Our studies provide a rationale for the use of non-continuous treatment to provide optimal therapy for PV patients.

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Polycythemia vera (PV) is a myeloproliferative disorder involving hematopoietic stem cells. A recurrent somatic missense mutation in JAK2 (JAK2V617F) is thought to play a causal role in PV. Therefore, targeting Jak2 will likely provide a molecular mechanism-based therapy for PV. To facilitate the development of such new and specific therapeutics, a suitable and well-characterized preclinical animal model is essential. Although several mouse models of PV have been reported, the spatiotemporal kinetics of PV formation and progression has not been studied. To address this, we created a bone marrow transplant mouse model that co-expresses mutant Jak2 and luciferase 2 (Luc2) genes. Bioluminescent imaging (BLI) was used to visualize disease cells and analyze the kinetics of PV development in vivo. To better understand the molecular mechanism of PV, we generated mice carrying a kinase inactive mutant Jak2 (Jak2K882E), demonstrating that the PV disease was dependent on constitutive activation of the Jak2 kinase activity. We further showed that the Jak2V617F mutation caused increased stem cell renewal activity and impaired cell differentiation, which was at least in part due to deregulated transcriptional programming. The Jak2V617F-Luc2 PV mice will be a useful preclinical model to characterize novel JAK2 inhibitors for the treatment of PV.