Discovery of a potent and selective CBP bromodomain inhibitor (Y08262) for treating acute myeloid leukemia

Bioorg Chem. 2024 Jan:142:106950. doi: 10.1016/j.bioorg.2023.106950. Epub 2023 Oct 30.

Abstract

The bromodomain of CREB (cyclic-AMP response element binding protein) binding protein (CBP) is an epigenetic "reader" and plays a key role in transcriptional regulation. CBP bromodomain is considered to be a promising therapeutic target for acute myeloid leukemia (AML). Herein, we report the discovery of a series of 1-(indolizin-3-yl)ethan-1-one derivatives as potent, and selective CBP bromodomain inhibitors focused on improving cellular potency. One of the most promising compounds, 7e (Y08262), inhibits the CBP bromodomain at the nanomolar level (IC50 = 73.1 nM) with remarkable selectivity. In addition, the new inhibitor also displays potent inhibitory activities in AML cell lines. Collectively, this study provides a new lead compound for further validation of CBP bromodomain as a molecular target for AML drug development.

Keywords: 1-(Indolizin-3-yl)ethan-1-one; Acute myeloid leukemia; Bromodomain inhibitor; CBP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Humans
  • Indolizines* / chemistry
  • Indolizines* / isolation & purification
  • Indolizines* / pharmacology
  • Leukemia, Myeloid, Acute* / drug therapy
  • Protein Domains
  • Pyrazoles* / chemistry
  • Pyrazoles* / isolation & purification
  • Pyrazoles* / pharmacology

Substances

  • 3-acetyl-N-(3-(1-cyclopropylpyrazol-4-yl)-2-fluorophenyl)-7-methoxyindolizine-1-carboxamide
  • Indolizines
  • Pyrazoles