2. Academic Validation
  3. Discovery of tetrahydrofuranyl spirooxindole-based SMYD3 inhibitors against gastric cancer via inducing lethal autophagy

Discovery of tetrahydrofuranyl spirooxindole-based SMYD3 inhibitors against gastric cancer via inducing lethal autophagy

  • Eur J Med Chem. 2023 Jan 15;246:115009. doi: 10.1016/j.ejmech.2022.115009.
Hong-Ping Zhu 1,  Jinlong Chai 2,  Rui Qin 3,  Hai-Jun Leng 4,  Xiang Wen 2,  Cheng Peng 5,  Gu He 6,  Bo Han 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu, 610106, China.
  • 2 Department of Dermatology and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 3 State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
  • 4 Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu, 610106, China.
  • 5 State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China. Electronic address: [email protected].
  • 6 Department of Dermatology and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China; Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology (CIII), Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China. Electronic address: [email protected].
  • 7 State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China. Electronic address: [email protected].
PMID: 36527933 DOI: 10.1016/j.ejmech.2022.115009
Abstract

SMYD3 is a Histone Methyltransferase involved in transcriptional regulation, and its overexpression in various forms of Cancer justifies that blocking SMYD3 functions can serve as a novel therapeutic strategy in Cancer treatment. Herein, a series of novel tetrahydrofuranyl spirooxindoles were designed and synthesized based on a structure-based drug design strategy. Subsequent biochemical analysis suggested that these novel SMYD3 inhibitors showed good Anticancer activity against stomach adenocarcinoma both in vitro and in vivo. Among them, compound 7r exhibited potent inhibitory capacities against SMYD3 and BGC823 cells with IC50 values of 0.81 and 0.75 μM, respectively. Mechanistic investigations showed that 7r could suppress Akt methylation and activation by SMYD3 and trigger lethal autophagic flux inhibition via the Akt-mTOR pathway. Collectively, our results may bridge the rational discovery of privileged structures, epigenetic targeting of SMYD3, and regulation of autophagic cell death.

Keywords

Lethal autophagy; SMYD3 inhibitors; Structure-activity relationship; Tetrahydrofuranyl spirooxindoles.

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