Scientific publications

Design and Synthesis of Novel Epigenetic Inhibitors Targeting Histone Deacetylases, DNA Methyltransferase 1, and Lysine Methyltransferase G9a with In Vivo Efficacy in Multiple Myeloma. Scientific Publication

Mar 25, 2021 | Magazine: Journal of Medicinal Chemistry

Obdulia Rabal  1 , Edurne San José-Enériz  2 , Xabier Agirre  2 , Juan Antonio Sánchez-Arias  1 , Irene de Miguel  1 , Raquel Ordoñez  2 , Leire Garate  2 , Estíbaliz Miranda  2 , Elena Sáez  1 , Amaia Vilas-Zornoza  2 , Antonio Pineda-Lucena  1 , Ander Estella  1 , Feifei Zhang  3 , Wei Wu  3 , Musheng Xu  3 , Felipe Prosper  2   4 , Julen Oyarzabal  1


Abstract

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 analogues that simultaneously inhibit histone deacetylases (from a low nanomolar range) and DNA methyltransferase-1 (from a mid-nanomolar range, IC50 < 200 nM).

Additionally, 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 chemical probes, multitarget 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.

CITATION J Med Chem. 2021 Mar 25;64(6):3392-3426. doi: 10.1021/acs.jmedchem.0c02255. Epub 2021 Mar 4.