Journal Article

In-silico guided chemical exploration of KDM4A fragments hits

Sabbatella, Raffaele, De Simone, Giada, Altucci, Lucia, De Rosa, Maria, Vallone, Rosario, Sarno, Federica, Fogazza, Mario, Cimino, Maura, Di Martino, Simona, Coronnello, Claudia, Cipollina, Chiara, Morando, Maria Agnese, Lombino, Jessica, Gulotta, Maria Rita, Perricone, Ugo, Alfano, Caterina

2023

Overview

Background Lysine demethylase enzymes (KDMs) are an emerging class of therapeutic targets, that catalyse the removal of methyl marks from histone lysine residues regulating chromatin structure and gene expression. KDM4A isoform plays an important role in the epigenetic dysregulation in various cancers and is linked to aggressive disease and poor clinical outcomes. Despite several efforts, the KDM4 family lacks successful specific molecular inhibitors. Results Herein, starting from a structure-based fragments virtual screening campaign we developed a synergic framework as a guide to rationally design efficient KDM4A inhibitors. Commercial libraries were used to create a fragments collection and perform a virtual screening campaign combining docking and pharmacophore approaches. The most promising compounds were tested in-vitro by a Homogeneous Time-Resolved Fluorescence-based assay developed for identifying selective substrate-competitive inhibitors by means of inhibition of H3K9me3 peptide demethylation. 2-(methylcarbamoyl)isonicotinic acid was identified as a preliminary active fragment, displaying inhibition of KDM4A enzymatic activity. Its chemical exploration was deeply investigated by computational and experimental approaches which allowed a rational fragment growing process. The in-silico studies guided the development of derivatives designed as expansion of the primary fragment hit and provided further knowledge on the structure–activity relationship. Conclusions Our study describes useful insights into key ligand-KDM4A protein interaction and provides structural features for the development of successful selective KDM4A inhibitors.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Biomedical and Life Sciences / Biomedicine / Chromatin / Crystal structure / Demethylation / Drug discovery / Enzymatic activity / Enzymes / Epigenetic inheritance / Epigenetic regulation / Epigenetics / Fragment-based drug discovery (FBDD) / Gene amplification / Gene expression / Gene Function / Genes / Health aspects / Histones / Human Genetics / KDM4 inhibitors / KDM4A / Lysine / Lysine demethylases / NMR / Nuclear magnetic resonance / Optimization / Peptides / Proteins / Rational drug design / Therapeutic targets