Design and synthesis of N-(1-(6-(substituted phenyl)-pyridazin-3-yl)-piperidine-3-yl)-amine derivatives as JMJD6 inhibitors

Bioorg Chem. 2022 Dec:129:106119. doi: 10.1016/j.bioorg.2022.106119. Epub 2022 Sep 13.

Abstract

JMJD6 is a member of the JmjC domain-containing family and has been identified as a promising therapeutic target for treating estrogen-induced and triple-negative breast cancer. To develop novel anti-breast cancer agents, we synthesized a class of N-(1-(6-(substituted phenyl)-pyridazine-3-yl)-piperidine-3-yl)-amine derivatives as potential JMJD6 inhibitors. Among them, the anti-cancer compound A29 was an excellent JMJD6 binder (KD = 0.75 ± 0.08 μM). It could upregulate the mRNA and protein levels of p53 and its downstream effectors p21 and PUMA by inhibiting JMJD6. Besides, A29 displayed potent anti-proliferative activities against tested breast cancer cells by the induction of cell apoptosis and cell cycle arrest. Significantly, A29 also promoted a remarkable reduction in tumor growth, with a TGI value of 66.6% (50 mg/kg, i.p.). Taken together, our findings suggest that A29 is a potent JMJD6 inhibitor bearing a new scaffold acting as a promising drug candidate for the treatment of breast cancer.

Keywords: Breast cancer, antitumor agent; JMJD6 inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amines / pharmacology
  • Antineoplastic Agents* / pharmacology
  • Apoptosis
  • Cell Cycle Checkpoints
  • Cell Line, Tumor
  • Cell Proliferation
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / genetics
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • Jumonji Domain-Containing Histone Demethylases / pharmacology
  • Piperidines / pharmacology
  • Triple Negative Breast Neoplasms* / pathology

Substances

  • Jumonji Domain-Containing Histone Demethylases
  • Piperidines
  • Antineoplastic Agents
  • Amines
  • JMJD6 protein, human