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Please use this identifier to cite or link to this item:
http://ir.nhri.org.tw/handle/3990099045/15920
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| Title: | Discovery of dual MER/AXL kinase inhibitors as bifunctional small molecules for inhibiting tumor growth and enhancing tumor immune microenvironment |
| Authors: | Li, MC;Lai, YL;Kuo, PH;Reddy, JS;Chen, CM;Manimala, J;Wang, PC;Wu, MS;Chang, CY;Yang, CM;Lin, CY;Huang, YC;Chiu, CH;Chang, L;Lin, WH;Yeh, TK;Yen, WC;Hsieh, HP |
| Contributors: | Institute of Biotechnology and Pharmaceutical Research |
| 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. |
| Date: | 2024-06-24 |
| Relation: | Journal of Medicinal Chemistry. 2024 Jun 24;Article in Press. |
| Link to: | http://dx.doi.org/10.1021/acs.jmedchem.4c00400 |
| JIF/Ranking 2023: | http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0022-2623&DestApp=IC2JCR |
| Cited Times(WOS): | https://www.webofscience.com/wos/woscc/full-record/WOS:001253308900001 |
| Cited Times(Scopus): | https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85196801981 |
| Appears in Collections: | [謝興邦] 期刊論文
[顏婉菁] 期刊論文
[葉燈光] 期刊論文
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| ISI001253308900001.pdf | | 8286Kb | Adobe PDF | 73 | View/Open |
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