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

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 -