Bianca Laura Bernardoni, Ilaria D'Agostino, Sonia Siragusa, Mattia Mori, Silvia Garavaglia, Concettina La Motta
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A scaffold repositioning approach: dihydroBenzoImidazoTriazineDione (BITD) derivatives as selective ALDH1A1 inhibitors.
The overexpression of the Aldehyde Dehydrogenases 1A subfamily (ALDH1As) in various diseases, particularly in cancer, has made it an important target for therapeutic applications. Interestingly, the 1A1 isoenzyme plays a role in tumor initiation and progression, being identified as a biomarker for cancer stem cells. However, although promising, current ALDH1A1 inhibitors suffer from a lack of isoform selectivity and off-target toxicity. This study aims to address these limitations by developing a new class of ALDH1A1-selective inhibitors. By leveraging structural analogies with Isatin-based ALDH1A1 inhibitors, we designed compounds containing a dihydrobenzo[4,5]imidazo[2,1-c][1,2,4]triazine-3,4-dione (BITD) core, that emerged from a repositioning approach. Using a microwave-assisted protocol, a small library of derivatives was synthesized, and enzymatic assays highlighted a promising isoform specificity for ALDH1A1 among ALDH1As, with the best-in-class compound 5, showing an inhibition of the enzyme activity of 86% for ALDH1A1 and no inhibition for 1A2 and 1A3 isoenzymes. In silico studies further elucidated the binding mode of 5, providing a rational basis for the observed selectivity. These findings represent a promising strategy for the development of more selective ALDH1A1 inhibitors, laying the foundation for further optimization processes.
期刊介绍:
Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including:
combinatorial chemistry and parallel synthesis;
small molecule libraries;
microwave synthesis;
flow synthesis;
fluorous synthesis;
diversity oriented synthesis (DOS);
nanoreactors;
click chemistry;
multiplex technologies;
fragment- and ligand-based design;
structure/function/SAR;
computational chemistry and molecular design;
chemoinformatics;
screening techniques and screening interfaces;
analytical and purification methods;
robotics, automation and miniaturization;
targeted libraries;
display libraries;
peptides and peptoids;
proteins;
oligonucleotides;
carbohydrates;
natural diversity;
new methods of library formulation and deconvolution;
directed evolution, origin of life and recombination;
search techniques, landscapes, random chemistry and more;