The Highly Potent Bromodomain (Brd) Inhibitor Fv-281 Displays Preclinical Efficacy In Acute Myeloid Leukemia (Aml)
BLOOD(2015)
摘要
Recent studies have demonstrated the therapeutic potential of targeting BRD2, BRD3 and BRD4 in hematological malignancies including AML. Here, we report a novel orally bioavailable BRD inhibitor, FV-281, that displays preclinical efficacy in AML in vitro and in vivo . In a binding screen assay of 32 bromodomains (BromoScan TM ), FV-281 selectively bound BRD2, BRD3 and BRD4 with K d values of 2.7 to 7.3 nM and was 2-5 fold more potent than the leading bromodomain inhibitor, OTX015. In AML cell lines (OCI-AML2, Tex, HL-60 and MV4-11), FV-281 reduced cell growth and viability after 72 hour incubation with IC 50 values 50 values u003e 10 µM. In contrast, FV-281 induced cell death as measured by Annexin V/PI staining in 3 of 4 primary AML samples with IC 50 values Within 4 hours of incubation with FV-281, c-Myc mRNA and protein level in OCI-AML2 cells were reduced by u003e95% and u003e80%, respectively. Following FV-281 washout, c-Myc protein expression returned to baseline within 20 hours with no loss of cell viability observed. Thus, the FV-281 is a reversible bromodomain inhibitor and sustained target inhibition is required to induce cell death. Likewise, after 6 and 48 hours of incubation with OCI-AML2 cells, FV-281 reduced Bcl-2 mRNA and protein level by u003e60% and u003e90%, respectively. To assess in vivo efficacy and toxicity, MV4-11 AML cells were engrafted subcutaneously in NOD-SCID mice (n=10). Once tumors were palpable, mice were treated with FV-281 orally (30mg/kg/d x 2 weeks) or vehicle control. FV-281 suppressed tumor growth without evidence of overt toxicity. In addition, primary AML cells were engrafted into the femurs of NOD-SCID mice (n=10). Three weeks after implantation, mice were treated with FV-281 orally (30mg/kg, 5 of 7 days, x 4 weeks) or vehicle control. FV-281 decreased AML engraftment in the injected and non-injected femur without evidence of overt toxicity (% human CD45 + /CD19 - /CD33 + in non-injected femur treated vs control: 20% vs 60%, p Thus, FV-281 is a novel oral reversible bromodomain inhibitor with significant in vivo activity in murine models of AML. These data support evaluation of this agent in upcoming phase I clinical trials. Disclosures Wang: Fluorinov Pharma Inc.: Employment. Dove: Fluorinov Pharma Inc.: Employment. Hadri: Fluorinov Pharma Inc.: Employment. O9Neill: Fluorinov Pharma Inc.: Employment. Slassi: Fluorinov Pharma Inc.: Employment.
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