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Discovery of Dual MER/AXL Kinase Inhibitors as Bifunctional Small Molecules for Inhibiting Tumor Growth and Enhancing Tumor Immune Microenvironment.
Li, Mu-Chun; Lai, You-Liang; Kuo, Po-Hsien; Reddy, Julakanti Satyanarayana; Chen, Chih-Ming; Manimala, Julakanti; Wang, Pei-Chen; Wu, Ming-Shiem; Chang, Chun-Yu; Yang, Chen-Ming; Lin, Chin-Yu; Huang, Yu-Chen; Chiu, Chun-Hsien; Chang, Ling; Lin, Wen-Hsing; Yeh, Teng-Kuang; Yen, Wan-Ching; Hsieh, Hsing-Pang.
Afiliación
  • Li MC; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan, ROC.
  • Lai YL; Biomedical Translation Research Center (BioTReC), Academia Sinica, Taipei City 115202, Taiwan, ROC.
  • Kuo PH; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan, ROC.
  • Reddy JS; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan, ROC.
  • Chen CM; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan, ROC.
  • Manimala J; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan, ROC.
  • Wang PC; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan, ROC.
  • Wu MS; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan, ROC.
  • Chang CY; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan, ROC.
  • Yang CM; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan, ROC.
  • Lin CY; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan, ROC.
  • Huang YC; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan, ROC.
  • Chiu CH; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan, ROC.
  • Chang L; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan, ROC.
  • Lin WH; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan, ROC.
  • Yeh TK; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan, ROC.
  • Yen WC; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan, ROC.
  • Hsieh HP; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan, ROC.
J Med Chem ; 67(13): 10906-10927, 2024 Jul 11.
Article en En | MEDLINE | ID: mdl-38913493
ABSTRACT
A series of bifunctional compounds have been discovered for their dual functionality as MER/AXL inhibitors and immune modulators. The furanopyrimidine scaffold, renowned for its suitability in kinase inhibitor discovery, offers at least three distinct pharmacophore access points. Insights from molecular modeling studies guided hit-to-lead optimization, which revealed that the 1,3-diketone side chain hybridized with furanopyrimidine scaffold that respectively combined amino-type substituent and 1H-pyrazol-4-yl substituent on the top and bottom of the aryl regions to produce 22 and 33, exhibiting potent antitumor activities in various syngeneic and xenograft models. More importantly, 33 demonstrated remarkable immune-modulating activity by upregulating the expression of total T-cells, cytotoxic CD8+ T-cells, and helper CD4+ T-cells in the spleen. These findings underscored the bifunctional capabilities of 33 (BPR5K230) with excellent oral bioavailability (F = 54.6%), inhibiting both MER and AXL while modulating the tumor microenvironment and highlighting its diverse applicability for further studies to advance its therapeutic potential.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Proto-Oncogénicas / Proteínas Tirosina Quinasas Receptoras / Inhibidores de Proteínas Quinasas / Microambiente Tumoral / Tirosina Quinasa c-Mer / Tirosina Quinasa del Receptor Axl / Antineoplásicos Límite: Animals / Female / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Proto-Oncogénicas / Proteínas Tirosina Quinasas Receptoras / Inhibidores de Proteínas Quinasas / Microambiente Tumoral / Tirosina Quinasa c-Mer / Tirosina Quinasa del Receptor Axl / Antineoplásicos Límite: Animals / Female / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos