Fragment-Based Discovery of a Selective and Cell-Active Benzodiazepinone CBP/EP300 Bromodomain Inhibitor (CPI-637)

Taylor, Alexander M.; Côté, Alexandre; Hewitt, Michael C.; Pastor, Richard; Leblanc, Yves; Nasveschuk, Christopher G.; Romero, F. Anthony; Crawford, Terry D.; Cantone, Nico; Jayaram, Hariharan; Setser, J.W.; Murray, J.M.; Beresini, Maureen H.; Boenig, Gladys de Leon; Chen, Zhongguo; Conery, Andrew R.; Cummings, Richard; Dakin, Leslie A.; Flynn, E. Megan; Huang, Oscar W.; Kaufman, Susan; Keller, Patricia J.; Kiefer, James R.; Lai, Tommy; Li, Yingjie; Liao, Jiangpeng; Liu, Wenfeng; Lu, Henry Horng Shing; Pardo, Eneida; Tsui, Vickie; Wang, Jian; Wang, Yongyun; Xu, Zhijun; Fen, Yan; Yu, Dong; Zawadzke, Laura E.; Zhu, Xiaoqin; Zhu, Xiaoyu; Sims, Robert J.; Cochran, Andrea G.; Bellon, S.F.; Audia, James E.; Magnuson, Steven; Albrecht, Brian K.

doi:10.1021/acsmedchemlett.6b00075

Cited by 102 publications

(78 citation statements)

References 33 publications

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“…All biochemical assay protocols were carried out as described previously (22)(23)(24). Binding of biotinylated small-molecule ligands to recombinant His-tagged bromodomains was assessed by time-resolved fluorescence resonance energy transfer (TR-FRET).…”

Section: Inhibitor Characterization and Usementioning

confidence: 99%

“…A bioluminescence resonance energy transfer (BRET) assay was used to measure cellular engagement of CBP by GNE-049 through disruption of the interaction between a tagged histone H3 construct and a CBP-luciferase construct in transfected HEK293 cells. The assay was carried out as described previously (22). To determine the inhibition of MYC expression, MV-4-11 cells were plated at 10,000 cells per well in 96-well plates in RPMI1640 media supplemented with 10% FBS and 2 mmol/L L-glutamine.…”

Section: Inhibitor Characterization and Usementioning

confidence: 99%

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Therapeutic Targeting of the CBP/p300 Bromodomain Blocks the Growth of Castration-Resistant Prostate Cancer

Jin¹,

Garcia²,

Chan³

et al. 2017

Cancer Research

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129

106

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Resistance invariably develops to antiandrogen therapies used to treat newly diagnosed prostate cancers, but effective treatments for castration-resistant disease remain elusive. Here, we report that the transcriptional coactivator CBP/p300 is required to maintain the growth of castration-resistant prostate cancer. To exploit this vulnerability, we developed a novel small-molecule inhibitor of the CBP/p300 bromodomain that blocks prostate cancer growth in vitro and in vivo. Molecular dissection of the consequences of drug treatment revealed a critical role for CBP/p300 in histone acetylation required for the transcriptional activity of the androgen receptor and its target gene expression. Our findings offer a preclinical proof of concept for small-molecule therapies to target the CBP/p300 bromodomain as a strategy to treat castrationresistant prostate cancer. Cancer Res; 77(20); 5564-75. Ó2017 AACR.

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Section: Inhibitor Characterization and Usementioning

confidence: 99%

Section: Inhibitor Characterization and Usementioning

confidence: 99%

Therapeutic Targeting of the CBP/p300 Bromodomain Blocks the Growth of Castration-Resistant Prostate Cancer

Jin¹,

Garcia²,

Chan³

et al. 2017

Cancer Research

Self Cite

129

106

View full text Add to dashboard Cite

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“…CPI-637 (34), aC REBBP/EP300 inhibitor based around a benzo [1,4]-diazepin-2-one scaffold, has been reported by Genentech and Constellation Pharmaceuticals (Figure 7d). [58] A fragment screening of % 2000 compounds in at hermal shift assay was used to identify hit compound 33,c hosen for displaying potencya tC REBBP (pIC 50 = 4.5) and 7-fold selectivity over the BET subfamily. X-ray crystallography identified the lactam portion of the benzo [1,4]-diazepin-2-one to be functioning as the KAc mimetic, with the expectedh ydrogen and water-mediated hydrogen bond interactions to the conserved Asn and Tyr, respectively observed.…”

Section: Crebbp/ep300mentioning

confidence: 99%

Advancements in the Development of non‐BET Bromodomain Chemical Probes

et al. 2019

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The bromodomain and extra terminal (BET) family of bromodomain‐containing proteins (BCPs) have been the subject of extensive research over the past decade, resulting in a plethora of high‐quality chemical probes for their tandem bromodomains. In turn, these chemical probes have helped reveal the profound biological role of the BET bromodomains and their role in disease, ultimately leading to a number of molecules in active clinical development. However, the BET subfamily represents just 8/61 of the known human bromodomains, and attention has now expanded to the biological role of the remaining 53 non‐BET bromodomains. Rapid growth of this research area has been accompanied by a greater understanding of the requirements for an effective bromodomain chemical probe and has led to a number of new non‐BET bromodomain chemical probes being developed. Advances since December 2015 are discussed, highlighting the strengths/caveats of each molecule, and the value they add toward validating the non‐BET bromodomains as tractable therapeutic targets.

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“… Beispiele für Fragmente und die daraus entwickelten Leitstrukturen ( 21 – 28 ) für Bromodomänen mit anspruchsvoller Ansteuerbarkeit (druggability) sowie deren Affinitätsprofil, Liganden‐Effizienz (LE) und Liganden‐Lipophilie‐Effizienz (LLE). Das Gerüst des ursprünglichen Fragments ist fett hervorgehoben.…”

Section: Fragment‐basierte Ansätze Für Die Entwicklung Potenter Und Sunclassified

Chemische Epigenetik: der Einfluss chemischer und chemo‐biologischer Techniken auf die Zielstruktur‐Validierung von Bromodomänen

Schiedel¹,

Moroglu²,

Ascough³

et al. 2019

Angewandte Chemie

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Viele Disziplinen befassen sich gegenwärtig mit Epigenetik, da diese von Bedeutung für viele biologische Vorgänge und pathologische Zustände ist. Auf molekularer Ebene fußen epigenetische Prozesse auf Modifizierungen in Nukleinbasen der DNA und RNA und/oder posttranslationalen Modifizierungen (PTMs) von Histonproteinen. Die Hinweise mehren sich, dass diese Modifikationen einer dynamischen Regulation unterliegen, mit einer zum Teil bereits identifizierten zellulären Maschinerie, die der Modulation und Interpretation dieser Markierungen dient. Wir konzentrieren uns hier auf Bromodomänen, die an acetylierte Lysinreste (KAc) binden. Fortschritte auf dem Gebiet der Bromodomänen und ihrer Liganden werden von vielen Disziplinen beflügelt, wobei der Chemie und der chemischen Biologie eine besondere Rolle zukommt. Hier werden die chemischen und chemo‐biologischen Schlüsseltechniken diskutiert, mit deren Hilfe Bromodomänen erforscht und Liganden der Bromodomänen entwickelt werden konnten – unabdingbare Voraussetzungen für die Validierung der Bromodomäne als therapeutisch sinnvolle Zielstruktur.

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Fragment-Based Discovery of a Selective and Cell-Active Benzodiazepinone CBP/EP300 Bromodomain Inhibitor (CPI-637)

Cited by 102 publications

References 33 publications

Therapeutic Targeting of the CBP/p300 Bromodomain Blocks the Growth of Castration-Resistant Prostate Cancer

Therapeutic Targeting of the CBP/p300 Bromodomain Blocks the Growth of Castration-Resistant Prostate Cancer

Advancements in the Development of non‐BET Bromodomain Chemical Probes

Chemische Epigenetik: der Einfluss chemischer und chemo‐biologischer Techniken auf die Zielstruktur‐Validierung von Bromodomänen

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