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Design, synthesis and evaluation of a pyrazolo[3,4-d]pyrimidine derivative as a novel and potent TGFß1R1 inhibitor.
Wang, Yubo; Liu, Yulin; Zhang, Yan; Zhang, Zixuan; Xu, Lei; Wang, Jiefu; Yang, Yijie; Hu, Biyu; Yao, Yuhong; Wei, Mingming; Wang, Junfeng; Tang, Bencan; Zhang, Kun; Liu, Shuangwei; Yang, Guang.
Afiliación
  • Wang Y; The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300071, PR China.
  • Liu Y; The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300071, PR China.
  • Zhang Y; The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300071, PR China.
  • Zhang Z; Department of Chemical and Environmental Engineering, Faculty of Science and Engineering, The University of Nottingham Ningbo China, Ningbo, 315100, PR China.
  • Xu L; Department of Urology, Tianjin Medical University General Hospital, Tianjin, 300050, PR China; Department of Urology, Zibo Central Hospital, Zibo, 255036, PR China.
  • Wang J; Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, PR China.
  • Yang Y; The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300071, PR China.
  • Hu B; Department of Chemical and Environmental Engineering, Faculty of Science and Engineering, The University of Nottingham Ningbo China, Ningbo, 315100, PR China.
  • Yao Y; The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300071, PR China.
  • Wei M; The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300071, PR China. Electronic address: mingmingshengwu@163.com.
  • Wang J; Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, PR China. Electronic address: wangjunfeng@tjmuch.com.
  • Tang B; Department of Chemical and Environmental Engineering, Faculty of Science and Engineering, The University of Nottingham Ningbo China, Ningbo, 315100, PR China. Electronic address: bencan.tang@nottingham.edu.cn.
  • Zhang K; The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300071, PR China. Electronic address: zhangkun1112@163.com.
  • Liu S; The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300071, PR China. Electronic address: shuangwei.liu@nankai.edu.cn.
  • Yang G; The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300071, PR China. Electronic address: guang.yang@nankai.edu.cn.
Eur J Med Chem ; 271: 116395, 2024 May 05.
Article en En | MEDLINE | ID: mdl-38626523
ABSTRACT
The transforming growth factor ß1 (TGFß1)/SMAD signaling pathway regulates many vital physiological processes. The development of potent inhibitors targeting activin receptor-like kinase 5 (ALK5) would provide potential treatment reagents for various diseases. A significant number of ALK5 inhibitors have been discovered, and they are currently undergoing clinical evaluation at various stages. However, the clinical demands were far from being met. In this study, we utilized an alternative conformation-similarity-based virtual screening (CSVS) combined with a fragment-based drug designing (FBDD) strategy to efficiently discover a potent and active hit with a novel chemical scaffold. After structural optimization in the principle of group replacement, compound 57 was identified as the most promising ALK5 inhibitor. Compound 57 demonstrated significant inhibitory effects against the TGF-ß1/SMAD signaling pathway. It could markedly attenuate the production of extracellular matrix (ECM) and deposition of collagen. Also, the lead compound showed adequate pharmacokinetic (PK) properties and good in vivo tolerance. Moreover, treatment with compound 57 in two different xerograph models showed significant inhibitory effects on the growth of pancreatic cancer cells. These results suggested that lead compound 57 refers as a promising ALK5 inhibitor both in vitro and in vivo, which merits further validation.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirazoles / Pirimidinas / Diseño de Fármacos / Inhibidores de Proteínas Quinasas / Receptor Tipo I de Factor de Crecimiento Transformador beta Límite: Animals / Humans Idioma: En Revista: Eur J Med Chem Año: 2024 Tipo del documento: Article Pais de publicación: Francia
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirazoles / Pirimidinas / Diseño de Fármacos / Inhibidores de Proteínas Quinasas / Receptor Tipo I de Factor de Crecimiento Transformador beta Límite: Animals / Humans Idioma: En Revista: Eur J Med Chem Año: 2024 Tipo del documento: Article Pais de publicación: Francia