Hit Optimization Of A Trypanosoma Cruzi Bromodomain Inhibitor Identified Using Combinatorial Chemistry

ALONSO, VICTORIA L.; ESCALANTE, ANDREA M.; FURLAN, RICARDO L. E.; SERRA, ESTEBAN

Mar del Plata

Encuentro; ANNUAL MEETING OF BIOSCIENCE SOCIETIES 2019; 2019

Recently, our group has used Dynamic Combinatorial Chemistry targeting the Trypanosoma cruzi Bromodomain factor 3 (TcBDF3), as a strategy for the identification of a parasite inhibitor. This hit is an acylhydrazone with a Kd of 1.7 M and and IC50 for epimastigotes, amastigotes and trypomastigotes between 13 and 23 uM. TcBDF3 interacts with acetylated α-tubulin present in the cytoskeleton and flagella of T. cruzi and is essential for the viability. TcBDF3 is an interesting target for the development of new trypanocidal drugs that disrupt the bromodomain-acetylated ligand interaction during the parasite differentiation. There are six other proteins with bromodomain in T. cruzi, among which TcBDF2 has also been shown to be essential for the parasite. Today it is a challenge to find selective inhibitors that can distinguish between the different bromodomains, and are more effective and less toxic than the trypanocidal drugs currently use.