EPIGENETIC TARGETED DRUG DISCOVERY: INHIBITORS OF METHYLTRANSFERASE G9A AND DUAL INHIBITORS OF G9A and HDAC

Ph.DDOCTOR OF PHILOSOPH

Monastrol mimic Biginelli dihydropyrimidinone derivatives: synthesis, cytotoxicity screening against HepG2 and HeLa cell lines and molecular modeling study

Biginelli dihydropyrimidinone derivatives as structural analogs of monastrol, a known human kinesin Eg5 inhibitor, were synthesized. IC(50) values of the synthesized compounds against the proliferation of human hepatocellular carcinoma and human epithelial carcinoma cell lines were determined through MTT assay. Molecular docking study gave a clear insight into the structural activity relationship of the compounds in comparison with monastrol

Discovery of a potent histone deacetylase (HDAC) 3/6 selective dual inhibitor

Herein, we report the discovery of a dual histone deacetylase inhibitor displaying a unique HDAC3/6 selectivity profile. An initial strategy to merge two epigenetic pharmacophores resulted in the discovery of potent HDAC6 inhibitors with selectivity over HDAC1. Screening in an HDAC panel revealed additional low nanomolar inhibition only against HDAC3. Low micromolar antiproliferative activities against two breast cancer and four hematological cancer cell lines was supported by pharmacodynamic studies on a preferred molecule, 24c, substantiating the HDAC inhibitory profile in cells. Apoptosis was identified as one of the main cell death pathways. Modelling studies of 24c against HDAC1,2,3 and 6 further provided insights on the orientation of specific residues relevant to compound potency, explaining the observed HDAC3/6 selectivity. A subset of the compounds also exhibited good antimalarial activities, particularly against the chloroquine-resistant strain K1 of P.falciparum. In vitro studies revealed a favourable DMPK profile warranting further investigation of the therapeutic potential of these compounds. (C) 2019 Elsevier Masson SAS. All rights reserved