New synthetic routes to Triazolo-benzodiazepine analogues: expanding the scope of the bump-and-hole approach for selective Bromo and Extra-Terminal (BET) bromodomain inhibition

Matthias G. J. Baud, Enrique Lin-Shiao, Michael Zengerle, Cynthia Tallant, Alessio Ciulli (Lead / Corresponding author)

Research output: Contribution to journalArticle

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Abstract

We describe new synthetic routes developed toward a range of substituted analogues of bromo and extra-terminal (BET) bromodomain inhibitors I-BET762/JQ1 based on the triazolo-benzodiazepine scaffold. These new routes allow for the derivatization of the methoxyphenyl and chlorophenyl rings, in addition to the diazepine ternary center and the side chain methylene moiety. Substitution at the level of the side chain methylene afforded compounds targeting specifically and potently engineered BET bromodomains designed as part of a bump and hole approach. We further demonstrate that marked selectivity for the second over the first bromodomain can be achieved with an indole derivative that exploits differential interaction with an aspartate/histidine conservative substitution on the BC loop of BET bromodomains.

Original languageEnglish
Pages (from-to)1492-1500
Number of pages9
JournalJournal of Medicinal Chemistry
Volume59
Issue number4
Early online date14 Sep 2015
DOIs
Publication statusPublished - 25 Feb 2016

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Benzodiazepines
Histidine
Aspartic Acid
indole
GSK525762A

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title = "New synthetic routes to Triazolo-benzodiazepine analogues: expanding the scope of the bump-and-hole approach for selective Bromo and Extra-Terminal (BET) bromodomain inhibition",
abstract = "We describe new synthetic routes developed toward a range of substituted analogues of bromo and extra-terminal (BET) bromodomain inhibitors I-BET762/JQ1 based on the triazolo-benzodiazepine scaffold. These new routes allow for the derivatization of the methoxyphenyl and chlorophenyl rings, in addition to the diazepine ternary center and the side chain methylene moiety. Substitution at the level of the side chain methylene afforded compounds targeting specifically and potently engineered BET bromodomains designed as part of a bump and hole approach. We further demonstrate that marked selectivity for the second over the first bromodomain can be achieved with an indole derivative that exploits differential interaction with an aspartate/histidine conservative substitution on the BC loop of BET bromodomains.",
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New synthetic routes to Triazolo-benzodiazepine analogues : expanding the scope of the bump-and-hole approach for selective Bromo and Extra-Terminal (BET) bromodomain inhibition. / Baud, Matthias G. J.; Lin-Shiao, Enrique; Zengerle, Michael; Tallant, Cynthia; Ciulli, Alessio (Lead / Corresponding author).

In: Journal of Medicinal Chemistry, Vol. 59, No. 4, 25.02.2016, p. 1492-1500.

Research output: Contribution to journalArticle

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T1 - New synthetic routes to Triazolo-benzodiazepine analogues

T2 - expanding the scope of the bump-and-hole approach for selective Bromo and Extra-Terminal (BET) bromodomain inhibition

AU - Baud, Matthias G. J.

AU - Lin-Shiao, Enrique

AU - Zengerle, Michael

AU - Tallant, Cynthia

AU - Ciulli, Alessio

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