1,721,773 research outputs found
Lead Optimization of Small Molecule ENL YEATS Inhibitors to Enable <i>In Vivo</i> Studies: Discovery of TDI-11055
No full textEleven-nineteen leukemia (ENL) is
an epigenetic reader protein
that drives oncogenic transcriptional programs in acute myeloid leukemia
(AML). AML is one of the deadliest hematopoietic malignancies, with
an overall 5-year survival rate of 27%. The epigenetic reader activity
of ENL is mediated by its YEATS domain that binds to acetyl and crotonyl
marks on histone tails and colocalizes with promoters of actively
transcribed genes that are essential for leukemia. Prior to the discovery
of TDI-11055, existing inhibitors of ENL YEATS showed in vitro potency, but had not shown efficacy in in vivo animal models. During the course of the medicinal
chemistry campaign described here, we identified ENL YEATS inhibitor TDI-11055 that has an improved pharmacokinetic profile and
is appropriate for in vivo evaluation of the ENL
YEATS inhibition mechanism in AML
Lead Optimization of Small Molecule ENL YEATS Inhibitors to Enable <i>In Vivo</i> Studies: Discovery of TDI-11055
No full textEleven-nineteen leukemia (ENL) is
an epigenetic reader protein
that drives oncogenic transcriptional programs in acute myeloid leukemia
(AML). AML is one of the deadliest hematopoietic malignancies, with
an overall 5-year survival rate of 27%. The epigenetic reader activity
of ENL is mediated by its YEATS domain that binds to acetyl and crotonyl
marks on histone tails and colocalizes with promoters of actively
transcribed genes that are essential for leukemia. Prior to the discovery
of TDI-11055, existing inhibitors of ENL YEATS showed in vitro potency, but had not shown efficacy in in vivo animal models. During the course of the medicinal
chemistry campaign described here, we identified ENL YEATS inhibitor TDI-11055 that has an improved pharmacokinetic profile and
is appropriate for in vivo evaluation of the ENL
YEATS inhibition mechanism in AML
Lead Optimization of Small Molecule ENL YEATS Inhibitors to Enable <i>In Vivo</i> Studies: Discovery of TDI-11055
No full textEleven-nineteen leukemia (ENL) is
an epigenetic reader protein
that drives oncogenic transcriptional programs in acute myeloid leukemia
(AML). AML is one of the deadliest hematopoietic malignancies, with
an overall 5-year survival rate of 27%. The epigenetic reader activity
of ENL is mediated by its YEATS domain that binds to acetyl and crotonyl
marks on histone tails and colocalizes with promoters of actively
transcribed genes that are essential for leukemia. Prior to the discovery
of TDI-11055, existing inhibitors of ENL YEATS showed in vitro potency, but had not shown efficacy in in vivo animal models. During the course of the medicinal
chemistry campaign described here, we identified ENL YEATS inhibitor TDI-11055 that has an improved pharmacokinetic profile and
is appropriate for in vivo evaluation of the ENL
YEATS inhibition mechanism in AML
Lead Optimization of Small Molecule ENL YEATS Inhibitors to Enable <i>In Vivo</i> Studies: Discovery of TDI-11055
No full textEleven-nineteen leukemia (ENL) is
an epigenetic reader protein
that drives oncogenic transcriptional programs in acute myeloid leukemia
(AML). AML is one of the deadliest hematopoietic malignancies, with
an overall 5-year survival rate of 27%. The epigenetic reader activity
of ENL is mediated by its YEATS domain that binds to acetyl and crotonyl
marks on histone tails and colocalizes with promoters of actively
transcribed genes that are essential for leukemia. Prior to the discovery
of TDI-11055, existing inhibitors of ENL YEATS showed in vitro potency, but had not shown efficacy in in vivo animal models. During the course of the medicinal
chemistry campaign described here, we identified ENL YEATS inhibitor TDI-11055 that has an improved pharmacokinetic profile and
is appropriate for in vivo evaluation of the ENL
YEATS inhibition mechanism in AML
Lead Optimization of Small Molecule ENL YEATS Inhibitors to Enable <i>In Vivo</i> Studies: Discovery of TDI-11055
No full textEleven-nineteen leukemia (ENL) is
an epigenetic reader protein
that drives oncogenic transcriptional programs in acute myeloid leukemia
(AML). AML is one of the deadliest hematopoietic malignancies, with
an overall 5-year survival rate of 27%. The epigenetic reader activity
of ENL is mediated by its YEATS domain that binds to acetyl and crotonyl
marks on histone tails and colocalizes with promoters of actively
transcribed genes that are essential for leukemia. Prior to the discovery
of TDI-11055, existing inhibitors of ENL YEATS showed in vitro potency, but had not shown efficacy in in vivo animal models. During the course of the medicinal
chemistry campaign described here, we identified ENL YEATS inhibitor TDI-11055 that has an improved pharmacokinetic profile and
is appropriate for in vivo evaluation of the ENL
YEATS inhibition mechanism in AML
Effect of MRLB-11055 in a Darbepoetin-Induced PV Efficacy Model.
No full text<p>The ability of MRLB-11055 to prevent darbepoetin-induced increases in hematocrit (Hct) and spleen mass (SPL) over 7 days is shown, as is the impact of MRLB-11055 on white blood cells (WBC) and its concentration in blood (PK). Dashed line indicates <i>in vivo</i> IC50 value.</p
Effect of MRLB-11055 on Target Tissue in JAK2 V617F-Luc2 Mice.
No full text<p>A. Time dependence of the effect of 54 mpk MRLB-11055 on key V617F-dependent endpoints. B. Correlation between BLI and CD71+TER119+ in spleen on Day 14 C. BLI recovery after treatment cessation on Day 7. D. Effect of MRLB-11055 on pSTAT5 in the spleen of V617F mice.</p
Effect of MRLB-11055 on JAK2-dependent cell lines grown <i>in vitro</i>.
No full text<p>A. Structure of MRLB-11055. B. Effect on proliferation of BaF3 JAK2 V617F cells over 48 hours. C. Effect on phosphoSTAT5 levels in JAK2-expressing BaF3 cells. D. Effect of 75 nM MRLB-11055 on level of apoptosis in BaF3 JAK2 cells over 48 hours.</p
Exposure and target engagement of MRLB-11055 in the peripheral blood of C57BL/6 mice stimulated with darbepoetin.
No full text<p>A. Effect of MRLB-11055 on phosphoSTAT5 levels at various times post-dose. B. Calculation of IC50 value for inhibition of phosphoSTAT5. C. PK of 3 doses of MRLB-11055 in mouse blood, with calculated IC50 superimposed (dashed line).</p
Effect of MRLB-11055 on major lymphoid populations in spleen of WT B6 mice.
No full text<p>MRLB-11055 was given for either 3 or 6 days (on), followed up by either a 0 or 4 day holiday (off), for up to 4 cycles. Effects on NK, B and T cells were measured by flow cytometry.</p
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