Discovery, Optimization, and Evaluation of Novel N-(Benzimidazol-5-yl)-1,3,4-thiadiazol-2-amine Analogues as Potent STAT3 Inhibitors for Cancer Treatment Article Swipe

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Ru Wang , Tingting Du , Wenqiang Liu , Yichen Liu , Y. H. Yang , Jinping Hu , Ming Ji , Beibei Yang , Li Li , Xiaoguang Chen ·

YOU? · · 2023 · Open Access · · DOI: https://doi.org/10.1021/acs.jmedchem.3c00863

Signal transducer and activator of transcription 3 (STAT3) is an attractive target for cancer therapy. However, identifying potent and selective STAT3 small-molecule inhibitors with drug-like properties remains challenging. Based on a scaffold combination strategy, compounds with a novel N-(benzimidazol-5-yl)-1,3,4-thiadiazol-2-amine scaffold were designed and their inhibition of the interleukin-6 (IL-6)/JAK/STAT3 pathway was tested in HEK-Blue IL-6 reporter cells. After optimization of lead compound 12, compound 40 was identified as a selective STAT3 inhibitor that directly binds the SH2 domain to inhibit STAT3 phosphorylation, translocation, and downstream gene transcription. Compound 40 exhibited antiproliferative activities against STAT3-overactivated DU145 (IC₅₀ value = 2.97 μM) and MDA-MB-231 (IC₅₀ value = 3.26 μM) cancer cells and induced cell cycle arrest and apoptosis. In the DU145 xenograft model, compound 40 showed in vivo antitumor efficacy following intraperitoneal administration, with a tumor growth inhibition rate of 65.3% at 50 mg/kg, indicating promise for further development.

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Chemistry DU145 STAT3 In vivo IC50 STAT protein Pharmacology Apoptosis Cancer cell Lead compound Biochemistry Cancer In vitro Biology Biotechnology LNCaP Genetics

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Type: article
Language: en
Landing Page: https://doi.org/10.1021/acs.jmedchem.3c00863
OA Status: green
Cited By: 13
References: 40
Related Works: 10
OpenAlex ID: https://openalex.org/W4385968395

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DOI: https://doi.org/10.1021/acs.jmedchem.3c00863

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Title: Discovery, Optimization, and Evaluation of Novel N-(Benzimidazol-5-yl)-1,3,4-thiadiazol-2-amine Analogues as Potent STAT3 Inhibitors for Cancer Treatment

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Type: article

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Language: en

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Publication year: 2023

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Publication date: 2023-08-18

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Authors: Ru Wang, Tingting Du, Wenqiang Liu, Yichen Liu, Y. H. Yang, Jinping Hu, Ming Ji, Beibei Yang, Li Li, Xiaoguang Chen

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Landing page: https://doi.org/10.1021/acs.jmedchem.3c00863

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Concepts: Chemistry, DU145, STAT3, In vivo, IC50, STAT protein, Pharmacology, Apoptosis, Cancer cell, Lead compound, Biochemistry, Cancer, In vitro, Biology, Biotechnology, LNCaP, Genetics

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Cited by: 13

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