Abstract
Rho family GTPases regulate cellular processes and promote tumour growth and metastasis; thus, RhoA is a potential target for tumour metastasis inhibition. However, limited progress has been made in the development of RhoA targeting anticancer drugs. Here, we synthesised benzo[b]thiophene-3-carboxylic acid 1,1-dioxide derivatives based on a covalent inhibitor of RhoA (DC-Rhoin), reported in our previous studies. The observed structure-activity relationship (contributed by carboxamide in C-3 and 1-methyl-1H-pyrazol in C-5) enhanced the anti-proliferative activity of the derivatives. Compound b19 significantly inhibited the proliferation, migration, and invasion of MDA-MB-231 cells and promoted their apoptosis. The suppression of myosin light chain phosphorylation and the formation of stress fibres confirmed the inhibitory activity of b19 via the RhoA/ROCK pathway. b19 exhibited a different binding pattern from DC-Rhoin, as observed in molecular docking analysis. This study provides a reference for the development of anticancer agents targeting the RhoA/ROCK pathway.
Keywords:
Benzo[b]thiophene-3-carboxylic acid 1,1-dioxide compounds; GTPases inhibitors; RhoA/ROCK pathway; anticancer activity.
MeSH terms
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Antineoplastic Agents* / chemical synthesis
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Antineoplastic Agents* / chemistry
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Antineoplastic Agents* / pharmacology
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Apoptosis* / drug effects
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Proliferation* / drug effects
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Dose-Response Relationship, Drug*
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Drug Screening Assays, Antitumor*
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Humans
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Molecular Docking Simulation
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Molecular Structure
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Structure-Activity Relationship
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Thiophenes* / chemical synthesis
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Thiophenes* / chemistry
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Thiophenes* / pharmacology
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rho-Associated Kinases* / antagonists & inhibitors
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rho-Associated Kinases* / metabolism
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rhoA GTP-Binding Protein* / antagonists & inhibitors
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rhoA GTP-Binding Protein* / metabolism
Substances
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Antineoplastic Agents
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rho-Associated Kinases
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rhoA GTP-Binding Protein
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Thiophenes
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RHOA protein, human
Grants and funding
The research was supported by the National Natural Science Foundation of China (No. 82474216); Natural Science Foundation of Guangdong Province (Nos. 2022A1515010103, 2023B1212060063, and 2023A1515220218); the Science and Technology Program of Guangzhou (Nos. 202002010004 and 202201020488); the Specific Research Fund for TCM Science and Technology of Guangdong Provincial Hospital of Chinese Medicine (No. YN2020QN02), Research Fund for Bajian Talents of Guangdong Provincial Hospital of Chinese Medicine (No. BJ2022KY08), and Special Funds for State Key Laboratory of Dampness Syndrome of Chinese Medicine (Nos. SZ2021ZZ33, and SZ2023ZZ13).