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Discovery of a Biologically Active Bromodomain Inhibitor by Target-Directed Dynamic Combinatorial Chemistry.


ABSTRACT: Target-directed dynamic combinatorial chemistry (DCC) has emerged as a strategy for the identification of inhibitors of relevant therapeutic targets. In this contribution, we use this strategy for the identification of a high-affinity binder of a parasite target, the Trypanosoma cruzi bromodomain-containing protein TcBDF3. This protein is essential for viability of T. cruzi, the protozoan parasite that causes Chagas disease. A small dynamic library of acylhydrazones was prepared from aldehydes and acylhydrazides at neutral pH in the presence of aniline. The most amplified library member shows (a) high affinity for the template, (b) interesting antiparasitic activity against different parasite forms, and (c) low toxicity against Vero cells. In addition, parasites are rescued from the compound toxicity by TcBDF3 overexpression, suggesting that the toxicity of this compound is due to the TcBDF3 inhibition, i.e., the binding event that initially drives the molecular amplification is reproduced in the parasite, leading to selective toxicity.

SUBMITTER: Garcia P 

PROVIDER: S-EPMC6187412 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Discovery of a Biologically Active Bromodomain Inhibitor by Target-Directed Dynamic Combinatorial Chemistry.

García Paula P   Alonso Victoria L VL   Serra Esteban E   Escalante Andrea M AM   Furlan Ricardo L E RLE  

ACS medicinal chemistry letters 20180911 10


Target-directed dynamic combinatorial chemistry (DCC) has emerged as a strategy for the identification of inhibitors of relevant therapeutic targets. In this contribution, we use this strategy for the identification of a high-affinity binder of a parasite target, the <i>Trypanosoma cruzi</i> bromodomain-containing protein <i>Tc</i>BDF3. This protein is essential for viability of <i>T. cruzi</i>, the protozoan parasite that causes Chagas disease. A small dynamic library of acylhydrazones was prep  ...[more]

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