Two Good Inhibitors-parp Inhibitor,olaparib,incb018424
PARP inhibitor olaparib is able to enhance a pre-existing DNA repair defect in ATM mutant lymphoid tumor cells, leading to the accumulation of unrepaired DNA DSBs and apoptotic-independent cell death, which involved the process of mitotic catastrophe. The growth of ATM mutant Granta-519 tumor cells in a NOD/SCID xenograft model was significantly impaired in the presence of olaparib, both in primary lymphoid organs as well as in subcutaneous tumors. Furthermore, the overall survival of the Granta-519engrafted NOS/SCID mice was significantly increased by olaparib treatment compared with mice receiving vehicle alone. Overall, olaparib impedes the growth of ATM mutant cells in vitro and in vivo by instigating the accumulation of intolerable levels of DNA damage in cycling cells. Olaparib alone and in combination with carboplatin greatly inhibit growth in BRCA2-mutated ovarian serous carcinoma. This effect was not observed in a serous carcinoma with normal BRCA function, showing a specific antitumor effect of olaparib in mutation carriers. Immunohistochemistry (cleaved caspase-3 and Ki-67 stains) of remnant tissue after olaparib treatment revealed significantly decreased proliferation and increased apoptotic indices in these tumors compared with untreated controls. Furthermore, olaparib-treated tumors showed highly reduced PARP-1 activity that correlated with olaparib levels.
At nanomolar concentrations, INCB018424 inhibits JAK2V617F, STAT5, and ERK1/2 phosphorylation resulting in reduced cellular proliferation and the induction of apoptosis by JAK2V617F+ Ba/F3 cells. INCB018424 potently inhibited the proliferation of ex vivo expanded erythroid progenitors obtained from patients with JAK2V617F+ PV. In a murine model of JAK2V617F-driven malignancy, therapy with INCB018424 significantly reduced splenomegaly and increased survival. In addition, INCB018424 decreased circulating levels of proinflammatory cytokines, IL-6 and TNF-, which have been implicated in the pathogenesis of debilitating constitutional symptoms seen in advanced MPNs.Although animals were not cured of their disease, our results are consistent with those observed in BCR-ABL1driven mouse models.30 The in vivo efficacy of INCB018424 is unlikely to be impacted by selection for resistance mutations in JAK2 because in vitro studies in Ba/F3-EpoR-JAK2V617F cells suggest that resistant clones are extremely infrequent compared with those observed in BCR-ABL1expressing cells treated with imatinib. INCB018424 exhibited good oral bioavailability and dose-proportional systemic exposures. INCB018424 showed low oral dose clearance and a small volume of distribution, with an approximate 3-hour plasma half-life and insignificant accumulation following repeat dosing. A high-fat meal reduced INCB018424 Cmax by 24% but had little effect on INCB018424 AUC. INCB018424 was cleared primarily by metabolism with negligible renal excretion. The pharmacodynamics of INCB018424, evaluated by the inhibition of phosphorylated STAT3 following cytokine stimulation in whole blood, showed good correlation with INCB018424 plasma concentrations. A phase 2 study of INCB018424, an oral, selective JAK1/JAK2 inhibitor,in patients with advanced polycythemia vera (PV) and essential thrombocythemia refractory to hydroxyurea. All inhibitors are very potent. INCB018424 inhibited JAK1 and JAK2 and reduced plasma IL-6 and CD40 levels.
At nanomolar concentrations, INCB018424 inhibits JAK2V617F, STAT5, and ERK1/2 phosphorylation resulting in reduced cellular proliferation and the induction of apoptosis by JAK2V617F+ Ba/F3 cells. INCB018424 potently inhibited the proliferation of ex vivo expanded erythroid progenitors obtained from patients with JAK2V617F+ PV. In a murine model of JAK2V617F-driven malignancy, therapy with INCB018424 significantly reduced splenomegaly and increased survival. In addition, INCB018424 decreased circulating levels of proinflammatory cytokines, IL-6 and TNF-, which have been implicated in the pathogenesis of debilitating constitutional symptoms seen in advanced MPNs.Although animals were not cured of their disease, our results are consistent with those observed in BCR-ABL1driven mouse models.30 The in vivo efficacy of INCB018424 is unlikely to be impacted by selection for resistance mutations in JAK2 because in vitro studies in Ba/F3-EpoR-JAK2V617F cells suggest that resistant clones are extremely infrequent compared with those observed in BCR-ABL1expressing cells treated with imatinib. INCB018424 exhibited good oral bioavailability and dose-proportional systemic exposures. INCB018424 showed low oral dose clearance and a small volume of distribution, with an approximate 3-hour plasma half-life and insignificant accumulation following repeat dosing. A high-fat meal reduced INCB018424 Cmax by 24% but had little effect on INCB018424 AUC. INCB018424 was cleared primarily by metabolism with negligible renal excretion. The pharmacodynamics of INCB018424, evaluated by the inhibition of phosphorylated STAT3 following cytokine stimulation in whole blood, showed good correlation with INCB018424 plasma concentrations. A phase 2 study of INCB018424, an oral, selective JAK1/JAK2 inhibitor,in patients with advanced polycythemia vera (PV) and essential thrombocythemia refractory to hydroxyurea. All inhibitors are very potent. INCB018424 inhibited JAK1 and JAK2 and reduced plasma IL-6 and CD40 levels.
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