Untargeted Diversity-Oriented Synthesis for the Discovery of New Antitumor Agents: An Integrated Approach of Inverse Virtual Screening, Bioinformatics, and Omics for Target Deconvolution

Molecular diversity
is one of the most pursued objectives in drug
discovery, and diversity-oriented synthesis (DOS) perfectly responds
to the achievement of this goal. In this paper, we describe a DOS
approach applied to the antitumor field with the aim of identifying
new anticancer structures and their associated targets. To accomplish
this ambitious project, after an initial stage of phenotypic evaluation,
we set up an integrated platform of inverse virtual screening (IVS),
bioinformatics, and omics to predict the biological targets of the
most promising compounds 31 and 63. Several
proteins emerged from this study, and the most interesting ones were
assessed by biophysical and in cellulo experiments, leading to the
validation of six targets involved in calcium regulation, endoplasmic
reticulum stress, and apoptosis. This work allowed us to identify
two hit compounds with an interesting antitumor mechanism, but principally,
to validate our platform as a fruitful tool for untargeted DOS campaigns.