Rabal, Obdulia; San Jose-Eneriz, Edurne; Agirre, Xabier; Sanchez-Arias, Juan Antonio; de Miguel, Irene; Ordonez, Raquel; Garate, Leire; Miranda, Estibaliz; Saez, Elena; Vilas-Zornoza, Amaia; Pineda-Lucena, Antonio; Estella, Ander; Zhang, Feifei; Wu, Wei; Xu, Musheng; Prosper, Felipe; Oyarzabal, Julen published the artcile< Design and Synthesis of Novel Epigenetic Inhibitors Targeting Histone Deacetylases, DNA Methyltransferase 1, and Lysine Methyltransferase G9a with In Vivo Efficacy in Multiple Myeloma>, Category: pyrimidines, the main research area is histone deacetylases DNA methyltransferase G9a inhibitors multiple myeloma antitumor.
Concomitant inhibition of key epigenetic pathways involved in silencing tumor suppressor genes has been recognized as a promising strategy for cancer therapy. Herein, we report a first-in-class series of quinoline-based analogs that simultaneously inhibit histone deacetylases (from a low nanomolar range) and DNA methyltransferase-1 (from a mid-nanomolar range, IC50 < 200 nM). Addnl., lysine methyltransferase G9a inhibitory activity is achieved (from a low nanomolar range) by introduction of a key lysine mimic group at the 7-position of the quinoline ring. The corresponding epigenetic functional cellular responses are observed: histone-3 acetylation, DNA hypomethylation, and decreased histone-3 methylation at lysine-9. These chem. probes, multi-target epigenetic inhibitors, were validated against the multiple myeloma cell line MM1.S, demonstrating promising in vitro activity of 12a (CM-444) with GI50 of 32 nM, an adequate therapeutic window (>1 log unit), and a suitable pharmacokinetic profile. In vivo, 12a achieved significant antitumor efficacy in a xenograft mouse model of human multiple myeloma.
Journal of Medicinal Chemistry published new progress about Acetylation (histone H3). 89793-12-4 belongs to class pyrimidines, and the molecular formula is C7H7ClN2O2, Category: pyrimidines.
Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia