2. Academic Validation
  3. Discovery of novel tacrine derivatives as potent antiproliferative agents with CDKs inhibitory property

Discovery of novel tacrine derivatives as potent antiproliferative agents with CDKs inhibitory property

  • Bioorg Chem. 2022 Sep;126:105875. doi: 10.1016/j.bioorg.2022.105875.
Wenwu Liu 1,  Limeng Wu 2,  Deping Li 3,  Yaoguang Huang 2,  Mingyue Liu 4,  Wenjie Liu 2,  Caizhi Tian 2,  Xin Liu 4,  Xiaowen Jiang 4,  Xiaolong Hu 5,  Xudong Gao 6,  Zihua Xu 7,  Hongyuan Lu 8,  Qingchun Zhao 9
Affiliations

Affiliations

  • 1 Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, People's Republic of China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
  • 2 School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
  • 3 School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
  • 4 School of Life Sciences, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
  • 5 State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
  • 6 Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, People's Republic of China.
  • 7 Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, People's Republic of China; School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
  • 8 School of Pharmacy, China Medical University, Shenyang 110122, People's Republic of China. Electronic address: [email protected].
  • 9 Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, People's Republic of China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China; School of Life Sciences, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China. Electronic address: [email protected].
PMID: 35623141 DOI: 10.1016/j.bioorg.2022.105875
Abstract

Tacrine was the first approved drug by the FDA for the treatment of Alzheimer's disease (AD) but was withdrawn from the market due to its dose-dependent hepatotoxicity. Herein, we describe our efforts toward the discovery of a novel series of tacrine derivatives for Cancer therapeutics. Intensive structural modifications of tacrine led to the identification of N-(4-{9-[(3S)-3-aminopyrrolidin-1-yl]-5,6,7,8-tetrahydroacridin-2-yl}pyridin-2-yl)cyclopropanecarboxamide hydrochloride ((S)-45, ZLWT-37) as a potent antiproliferative agent (GI50 = 0.029 μM for HCT116). In addition, ZLWT-37 exhibited lower inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) compared to tacrine. The in vitro studies demonstrated that ZLWT-37 could significantly induce Apoptosis and arrest the cell cycle in the G2/M phase in HCT116 cells. The in vivo studies revealed that compound ZLWT-37 showed excellent antitumor efficacy in HCT116 xenograft tumor model and favorable pharmacokinetics profiles (F% = 28.70%) as well as low toxicity in the acute toxicity test with a median lethal dose (LD50) of 380.3 mg/kg. Encouragingly, ZLWT-37 had no obvious hepatotoxicity, nephrotoxicity, and hematologic toxicity. Kinase assay suggested that ZLWT-37 possessed potent cyclin-dependent kinase 9 (CDK9) inhibitory activity (IC50 = 0.002 μM) and good selectivity over CDK2 (IC50 = 0.054 μM). Collectively, these findings indicate that compound ZLWT-37 is a promising anti-cancer agent that deserves further preclinical evaluation.

Keywords

AChE; CDK2; CDK9; Cancer therapeutics; Tacrine.

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