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

doi:10.1002/anie.201705516

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)

Biological Chemistry and Drug Discovery

Research output: Contribution to journal › Article › peer-review

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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 language	English
Pages (from-to)	12476-12480
Number of pages	6
Journal	Angewandte Chemie International Edition
Volume	56
Issue number	41
Early online date	2 Aug 2017
DOIs	https://doi.org/10.1002/anie.201705516
Publication status	Published - 27 Sept 2017

Keywords

4-acyl pyrroles
bromodomains
CBP
drug discovery
p300

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "Beyond the BET family: targeting CBP/p300 with 4-acyl pyrroles",

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.",

keywords = "4-acyl pyrroles, bromodomains, CBP, drug discovery, p300",

author = "Martin H{\"u}gle and Xavier Lucas and Dmytro Ostrovskyi and Pierre Regenass and Stefan Gerhardt and Oliver Einsle and Mirjam Hau and Manfred Jung and Bernhard Breit and Stefan G{\"u}nther and Daniel Wohlwend",

note = "This work was financially supported by the DFG (GU1225/3-1, X. L., and WO2012/1-1, M. H.). S. G., D. O., B. B., M. J., and O. E. received funding from the DFG (CRC 992 {\textquoteleft}Medical Epigenetics{\textquoteright}). ",

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TY - JOUR

T1 - Beyond the BET family

T2 - targeting CBP/p300 with 4-acyl pyrroles

AU - Hügle, Martin

AU - Lucas, Xavier

AU - Ostrovskyi, Dmytro

AU - Regenass, Pierre

AU - Gerhardt, Stefan

AU - Einsle, Oliver

AU - Hau, Mirjam

AU - Jung, Manfred

AU - Breit, Bernhard

AU - Günther, Stefan

AU - Wohlwend, Daniel

N1 - This work was financially supported by the DFG (GU1225/3-1, X. L., and WO2012/1-1, M. H.). S. G., D. O., B. B., M. J., and O. E. received funding from the DFG (CRC 992 ‘Medical Epigenetics’).

PY - 2017/9/27

Y1 - 2017/9/27

N2 - 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.

AB - 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.

KW - 4-acyl pyrroles

KW - bromodomains

KW - CBP

KW - drug discovery

KW - p300

U2 - 10.1002/anie.201705516

DO - 10.1002/anie.201705516

M3 - Article

C2 - 28766825

SN - 1433-7851

VL - 56

SP - 12476

EP - 12480

JO - Angewandte Chemie International Edition

JF - Angewandte Chemie International Edition

IS - 41

ER -

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

Abstract

Keywords

UN SDGs

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