Beyond the BET family: targeting CBP/p300 with 4-acyl pyrroles

Martin Hügle, Xavier Lucas, Dmytro Ostrovskyi, Pierre Regenass, Stefan Gerhardt, Oliver Einsle, Mirjam Hau, Manfred Jung, Bernhard Breit, Stefan Günther, Daniel Wohlwend (Lead / Corresponding author)

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6 Citations (Scopus)
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Abstract

BET bromodomain inhibitors are widely used both as chemical tools to study the biological role of their targets in living organisms, and as candidates for drug development against several cancer variants and human disorders. However, non-BET bromodomains such as those in p300 and CBP are less studied. Here, we introduce XDM-CBP, a highly potent and selective inhibitor for the bromodomains of CBP and p300 derived from a pan-selective BET BRD-binding fragment. In addition to X-ray crystal structure analysis and thermodynamic profiling, we used XDM-CBP in in vitro cell screenings of several cancer cell lines to study its inhibitory potential on cancer cell proliferation. Our results demonstrate that XDM-CBP is a potent and selective CBP/p300 inhibitor that acts on specific cancer cell lines, in particular malignant melanoma, breast cancer, and leukemia.

Original languageEnglish
Pages (from-to)12476-12480
Number of pages6
JournalAngewandte Chemie International Edition
Volume56
Issue number41
Early online date2 Aug 2017
DOIs
Publication statusPublished - 27 Sep 2017

Keywords

  • 4-acyl pyrroles
  • bromodomains
  • CBP
  • drug discovery
  • p300

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    Hügle, M., Lucas, X., Ostrovskyi, D., Regenass, P., Gerhardt, S., Einsle, O., Hau, M., Jung, M., Breit, B., Günther, S., & Wohlwend, D. (2017). Beyond the BET family: targeting CBP/p300 with 4-acyl pyrroles. Angewandte Chemie International Edition, 56(41), 12476-12480. https://doi.org/10.1002/anie.201705516