Design, synthesis and biological evaluation of novel HDACs inhibitors based on pyrrolo[2,3-d]pyrimidine and pyrrolo[2,3-b]pyridine scaffolds.
Fiche publication
Date publication
mai 2023
Journal
ChemMedChem
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GARRIDO Carmen
Tous les auteurs :
Mao ND, Gao Y, Dang XW, Duan JL, Hui Z, Che H, Xu Y, Zhang H, He X, Garrido C, Ye XY
Lien Pubmed
Résumé
Histone deacetylases (HDACs) are validated targets for the development of anticancer drugs in epigenetics. We have designed and synthesized a series of novel HDACs inhibitors based on pyrrolo[2,3-d]pyrimidine and pyrrolo[2,3-b]pyridine scaffolds. Compound B3 exhibits potent inhibitory activity against HDAC1 and HDAC6 with IC50 values of 5.2 nM and 4.4 nM, respectively. It exhibited potent anti-proliferative effects against three tumour cell lines (IC50 = 0.13, 0.37, and 1.11 µM, MV-4-11, K562, and WSU-DLCL-2 respectively) with 2-6 fold improvement comparing to SAHA. Mechanistic studies on WSU-DLCL-2 cell reveal that B3 exhibits anticancer effects through induction of G0/G1 phase arrest and promotion of apoptosis. The result warrants further investigation of this series of compounds for the treatment of hematological malignancy.
Mots clés
Anticancer, Histone deacetylase, Inhibitor, hematological malignancy, novel drug design and synthesis
Référence
ChemMedChem. 2023 05 1;:e202200683