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
  • 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.

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