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

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机构： [1]State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China [2]Department of Dermatology and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China [3]Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu, 610106, China [4]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

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关键词： SMYD3 inhibitors Tetrahydrofuranyl spirooxindoles Structure-activity relationship Lethal autophagy

摘要：

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.Copyright © 2022 Elsevier Masson SAS. All rights reserved.

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出版当年[2022]版：

大类 | 1 区

医学

小类 | 1 区药物化学

最新[2023]版：

大类 | 2 区

医学

小类 | 1 区药物化学

第一作者：

第一作者机构： [1]State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China [3]Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu, 610106, China

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通讯作者：

通讯机构： [1]State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China [2]Department of Dermatology and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China [4]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 [*1]State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China. [*2]Department of Dermatology and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.

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

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