2. Academic Validation
  3. Discovery of ( S)- N-(2-Amino-4-fluorophenyl)-4-(1-(3-(4-((dimethylamino)methyl)phenyl)-6-oxopyridazin-1(6 H)-yl)ethyl)benzamide as Potent Class I Selective HDAC Inhibitor for Oral Anticancer Drug Candidate

Discovery of ( S)- N-(2-Amino-4-fluorophenyl)-4-(1-(3-(4-((dimethylamino)methyl)phenyl)-6-oxopyridazin-1(6 H)-yl)ethyl)benzamide as Potent Class I Selective HDAC Inhibitor for Oral Anticancer Drug Candidate

  • J Med Chem. 2023 May 25;66(10):7016-7037. doi: 10.1021/acs.jmedchem.3c00525.
Daqiang Li 1,  Zhuo Zhang 1 2 3,  Yalei Li 4,  Xinyi Wang 4 3,  Hanyue Zhong 1 3,  Huajie Yang 1,  Yong Xi 4,  Hongchun Liu 4,  Aijun Shen 4 3 5,  Youhong Hu 1 2 3 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zu-Chong-Zhi Road, Shanghai 201203, China.
  • 2 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 3 University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 110039, China.
  • 4 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zu-Chong-Zhi Road, Shanghai 201203, China.
  • 5 Lingang Laboratory, Shanghai 200031, China.
  • 6 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China.
PMID: 37184921 DOI: 10.1021/acs.jmedchem.3c00525
Abstract

A novel series of benzamide derivatives were successively designed and synthesized prepared from the pyridazinone scaffold. Among them, (S)-17b, demonstrated potent inhibitory activity in vitro toward human class I HDAC isoforms and human myelodysplastic syndrome (SKM-1) cell line. Also, (S)-17b strongly increased the intracellular level of acetyl-histone H3 and P21 simultaneously and effectively induced G1 cell cycle arrest and Apoptosis. Through oral dosing in SKM-1 xenograft models, (S)-17b exhibited excellent in vivo antitumor activity. In addition, compound (S)-17b showed better antitumor efficacy on mouse models with intact immune system than those with thymus deficiencies. Furthermore, this compound displayed a favorable pharmacokinetic profile in ICR mice and SD rat, respectively, minimal metabolic property differences among hepatocytes from five species, and a low inhibition upon the human ether-a-go-go (hERG) channel with an IC50 value of 34.6 μΜ. This novel compound (S)-17b may serve as a new drug candidate for further investigation.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-154855
    HDAC Inhibitor