Current chemoimmunotherapy is unable to cure up to 40% of patients diagnosed with diffuse large B-cell lymphoma (DLBCL). Targeting the mechanisms by which DLBCL evades apoptosis is crucial to overcoming treatment failure in this heterogeneous disease as both current and novel treatments depend on the apoptosis of malignant cells. Despite the common overexpression of BCL-2, venetoclax is ineffective in DLBCL due to MCL-1 co-expression. This is driven by pro-growth PI3-kinase signaling, which is promoted in turn by PIM kinases. In this study, the novel dual-kinase inhibitor, IBL-202, was combined with venetoclax against a panel of DLBCL cell lines that have variable expression of pro-survival proteins. The results support the efficacy of simultaneously targeting inter-related molecules to overcome apoptotic escape in this biologically heterogeneous disease. As venetoclax, pan-PIM-kinase and pan-PI3-kinase inhibitors have, or are currently being studied in clinical trials, it may be rational to consider these drugs in combination for the treatment of DLBCL.

2020-10-27·Blood Advances2区 · 医学

IBL-202 is synergistic with venetoclax in CLL under in vitro conditions that mimic the tumor microenvironment

2区 · 医学

Article

作者: Shen, Yandong ; Mulligan, Stephen P. ; O’Neill, Michael ; O’Dwyer, Michael ; Crassini, Kyle ; Christopherson, Richard I. ; Fatima, Narjis ; Best, O. Giles

AbstractThe B-cell receptor signaling pathway and dysregulation of the Bcl-2 family of proteins play crucial roles in the pathogenesis of chronic lymphocytic leukemia (CLL). Despite significant advances in the treatment of the disease, relapse and drug resistance are not uncommon. In the current study, we investigated the dual PI3/PIM kinase inhibitor IBL-202 in combination with venetoclax as a treatment option for CLL using both primary CLL cells and TP53-deficient OSU-CLL cells generated using the CRISPR-Cas9 system. IBL-202 and venetoclax were highly synergistic against primary CLL cells cocultured with CD40L fibroblasts (combination index [CI], 0.4, at a fractional effect of 0.9) and TP53-knockout (KO) OSU-CLL cells (CI, 0.5, at a fractional effect of 0.9). Synergy between the drugs was consistent, with a significant (P < .05) reduction in the 50% inhibitory concentration for both drugs. IBL-202 and venetoclax in combination induced cell-cycle arrest and slowed the proliferation of both wild-type and TP53-KO cell lines. The drug combination inhibited AKT phosphorylation, reduced expression of Bcl-xL and NF-κB, and increased the Noxa/Mcl-1 ratio. Downregulation of CXCR4 was consistent with inhibition of the SDF-1α–induced migratory capacity of CLL cells. Synergy between IBL-202 and venetoclax against primary CLL cells cultured under conditions that mimic the tumor microenvironment suggests this drug combination may be effective against CLL cells within the lymph nodes and bone marrow. Furthermore, the efficacy of the combination against the TP53-KO OSU-CLL cell line suggests the combination may be a highly effective treatment strategy for high-risk CLL.

2018-09-01·British Journal of Haematology2区 · 医学

The dual inhibitor of the phosphoinositol‐3 and PIM kinases, IBL‐202, is effective against chronic lymphocytic leukaemia cells under conditions that mimic the hypoxic tumour microenvironment

2区 · 医学

Article

作者: Christopherson, Richard ; Mulligan, Stephen ; Best, O. Giles ; Crassini, Kyle ; O'Neill, Michael ; Shen, Yandong ; O'Dwyer, Michael

SummaryDespite significant advances in treatment, chronic lymphocytic leukaemia (CLL) remains an incurable disease. Ibrutinib and idelalisib, which inhibit Bruton Tyrosine kinase (BTK) and phosphoinositol‐3 (PI3) kinase‐δ respectively, have become important treatment options for the disease and demonstrate the potential of targeting components of the B‐cell receptor‐signalling pathway. IBL‐202 is a dual inhibitor of the PIM and PI3 kinases. Synergy between the pan‐PIM inhibitor, pPIMi, and idelalisib against a range of haematological cell lines and primary CLL cells supports the rationale for preclinical studies of IBL‐202 in CLL. Importantly, IBL‐202, but not idelalisib, was cytotoxic against CLL cells under in vitro conditions that mimic the hypoxic tumour microenvironment. The significant effects of IBL‐202 on CD49d and CXCR4 expression and migration, cycle and proliferation of CLL cells suggest the drug may also interfere with the migratory and proliferative capacity of the leukaemic cells. Collectively, these data demonstrate that dual inhibition of the PIM and PI3 kinases by IBL‐202 may be an effective strategy for targeting CLL cells, particularly within the environmental niches known to confer drug‐resistance.

100 项与 ETP-539 相关的药物交易

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