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Controlling Intramolecular Interactions in the Design of Selective, High-Affinity Ligands for the CREBBP Bromodomain.
Brand, Michael; Clayton, James; Moroglu, Mustafa; Schiedel, Matthias; Picaud, Sarah; Bluck, Joseph P; Skwarska, Anna; Bolland, Hannah; Chan, Anthony K N; Laurin, Corentine M C; Scorah, Amy R; See, Larissa; Rooney, Timothy P C; Andrews, Katrina H; Fedorov, Oleg; Perell, Gabriella; Kalra, Prakriti; Vinh, Kayla B; Cortopassi, Wilian A; Heitel, Pascal; Christensen, Kirsten E; Cooper, Richard I; Paton, Robert S; Pomerantz, William C K; Biggin, Philip C; Hammond, Ester M; Filippakopoulos, Panagis; Conway, Stuart J.
Afiliación
  • Brand M; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
  • Clayton J; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
  • Moroglu M; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
  • Schiedel M; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
  • Picaud S; Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 3TA, U.K.
  • Bluck JP; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
  • Skwarska A; Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, U.K.
  • Bolland H; Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, U.K.
  • Chan AKN; Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, U.K.
  • Laurin CMC; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
  • Scorah AR; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
  • See L; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
  • Rooney TPC; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
  • Andrews KH; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
  • Fedorov O; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
  • Perell G; Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 3TA, U.K.
  • Kalra P; Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States.
  • Vinh KB; Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States.
  • Cortopassi WA; Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States.
  • Heitel P; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
  • Christensen KE; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
  • Cooper RI; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
  • Paton RS; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
  • Pomerantz WCK; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
  • Biggin PC; Department of Chemistry, Colorado State University, 1301 Center Ave, Ft. Collins, Colorado 80523-1872, United States.
  • Hammond EM; Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States.
  • Filippakopoulos P; Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, U.K.
  • Conway SJ; Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, U.K.
J Med Chem ; 64(14): 10102-10123, 2021 07 22.
Article en En | MEDLINE | ID: mdl-34255515
ABSTRACT
CREBBP (CBP/KAT3A) and its paralogue EP300 (KAT3B) are lysine acetyltransferases (KATs) that are essential for human development. They each comprise 10 domains through which they interact with >400 proteins, making them important transcriptional co-activators and key nodes in the human protein-protein interactome. The bromodomains of CREBBP and EP300 enable the binding of acetylated lysine residues from histones and a number of other important proteins, including p53, p73, E2F, and GATA1. Here, we report a work to develop a high-affinity, small-molecule ligand for the CREBBP and EP300 bromodomains [(-)-OXFBD05] that shows >100-fold selectivity over a representative member of the BET bromodomains, BRD4(1). Cellular studies using this ligand demonstrate that the inhibition of the CREBBP/EP300 bromodomain in HCT116 colon cancer cells results in lowered levels of c-Myc and a reduction in H3K18 and H3K27 acetylation. In hypoxia (<0.1% O2), the inhibition of the CREBBP/EP300 bromodomain results in the enhanced stabilization of HIF-1α.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Benzodiazepinonas / Diseño de Fármacos / Proteína de Unión a CREB / Proteína p300 Asociada a E1A / Bibliotecas de Moléculas Pequeñas Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2021 Tipo del documento: Article País de afiliación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Benzodiazepinonas / Diseño de Fármacos / Proteína de Unión a CREB / Proteína p300 Asociada a E1A / Bibliotecas de Moléculas Pequeñas Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2021 Tipo del documento: Article País de afiliación: Reino Unido