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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • DNA (Cytosine-5-)-Methyltransferase 1 / antagonists & inhibitors*
  • DNA (Cytosine-5-)-Methyltransferase 1 / metabolism
  • Drug Design
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Histocompatibility Antigens / metabolism
  • Histone Deacetylase Inhibitors / chemistry*
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylase Inhibitors / therapeutic use
  • Histone Deacetylases / metabolism
  • Histone-Lysine N-Methyltransferase / antagonists & inhibitors*
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Molecular Docking Simulation
  • Neoplasms / drug therapy
  • Neoplasms / metabolism

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Histocompatibility Antigens
  • Histone Deacetylase Inhibitors
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNMT1 protein, human
  • EHMT2 protein, human
  • Histone-Lysine N-Methyltransferase
  • Histone Deacetylases