Bruton’s tyrosine kinase (BTK) is a potential therapeutic target in acute myeloid leukemia (AML) and the small molecule BTK inhibitor ibrutinib has been found to potentiate the cytotoxic activity o...

19 Jan 2016·Oncotarget

Ibrutinib synergizes with poly(ADP-ribose) glycohydrolase inhibitors to induce cell death in AML cells via a BTK-independent mechanism

Article

Author: Rotin, Lianne E. ; MacLean, Neil ; Barber, Dwayne L. ; Schimmer, Aaron D. ; Lin, Feng-Hsu ; Slassi, Malik ; Minden, Mark D. ; Datti, Alessandro ; Wrana, Jeff ; Hurren, Rose ; Wang, XiaoMing ; Gronda, Marcela

Targeting Bruton's tyrosine kinase (BTK) with the small molecule BTK inhibitor ibrutinib has significantly improved patient outcomes in several B-cell malignancies, with minimal toxicity. Given the reported expression and constitutive activation of BTK in acute myeloid leukemia (AML) cells, there has been recent interest in investigating the anti-AML activity of ibrutinib. We noted that ibrutinib had limited single-agent toxicity in a panel of AML cell lines and primary AML samples, and therefore sought to identify ibrutinib-sensitizing drugs. Using a high-throughput combination chemical screen, we identified that the poly(ADP-ribose) glycohydrolase (PARG) inhibitor ethacridine lactate synergized with ibrutinib in TEX and OCI-AML2 leukemia cell lines. The combination of ibrutinib and ethacridine induced a synergistic increase in reactive oxygen species that was functionally important to explain the observed cell death. Interestingly, synergistic cytotoxicity of ibrutinib and ethacridine was independent of the inhibitory effect of ibrutinib against BTK, as knockdown of BTK did not sensitize TEX and OCI-AML2 cells to ethacridine treatment. Thus, our findings indicate that ibrutinib may have a BTK-independent role in AML and that PARG inhibitors may have utility as part of a combination therapy for this disease.

03 Dec 2015·Blood

The Highly Potent Bromodomain (BRD) Inhibitor FV-281 Displays Preclinical Efficacy in Acute Myeloid Leukemia (AML)

Author: Schimmer, Aaron D. ; MacLean, Neil ; Li, Janessa ; Skorupski, Clarissa ; Gronda, Marcela ; Minden, Mark D. ; Slassi, Malik ; Dove, Peter ; Shamas-Din, Aisha ; Bo, Feng ; Aman, Ahmed ; Al-awar, Rima ; Wang, Zezhou ; O'Neill, David ; Hurren, Rose ; Hadri, Wissam ; Wang, Xiaoming

AbstractRecent 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 (BromoScanTM), FV-281 selectively bound BRD2, BRD3 and BRD4 with Kd 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 IC50 values < 50 nM and was 6-fold more potent than OTX015. FV-281 was not cytotoxic to normal hematopoietic cells (n=4) with all IC50 values > 10 µM. In contrast, FV-281 induced cell death as measured by Annexin V/PI staining in 3 of 4 primary AML samples with IC50values < 850 nM.Within 4 hours of incubation with FV-281, c-Myc mRNA and protein level in OCI-AML2 cells were reduced by >95% and >80%, 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 >60% and >90%, 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<0.0001).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.DisclosuresWang: Fluorinov Pharma Inc.: Employment. Dove:Fluorinov Pharma Inc.: Employment. Hadri:Fluorinov Pharma Inc.: Employment. O'Neill:Fluorinov Pharma Inc.: Employment. Slassi:Fluorinov Pharma Inc.: Employment.

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