Discovery of a highly potent and orally available importin-β1 inhibitor that overcomes enzalutamide-resistance in advanced prostate cancer
Nuclear transporter importin-β1 is emerging as an attractive target by virtue of its prevalence in many cancers. However, the lack of druggable inhibitors restricts its therapeutic proof of concept. In the present work, we optimized a natural importin-β1 inhibitor DD1 to afford an improved analog DD...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | Acta Pharmaceutica Sinica B |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383523002794 |
| _version_ | 1827636285436592128 |
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| author | Jia-Luo Huang Xue-Long Yan Dong Huang Lu Gan Huahua Gao Run-Zhu Fan Shen Li Fang-Yu Yuan Xinying Zhu Gui-Hua Tang Hong-Wu Chen Junjian Wang Sheng Yin |
| author_facet | Jia-Luo Huang Xue-Long Yan Dong Huang Lu Gan Huahua Gao Run-Zhu Fan Shen Li Fang-Yu Yuan Xinying Zhu Gui-Hua Tang Hong-Wu Chen Junjian Wang Sheng Yin |
| author_sort | Jia-Luo Huang |
| collection | DOAJ |
| description | Nuclear transporter importin-β1 is emerging as an attractive target by virtue of its prevalence in many cancers. However, the lack of druggable inhibitors restricts its therapeutic proof of concept. In the present work, we optimized a natural importin-β1 inhibitor DD1 to afford an improved analog DD1-Br with better tolerability (>25 folds) and oral bioavailability. DD1-Br inhibited the survival of castration-resistant prostate cancer (CRPC) cells with sub-nanomolar potency and completely prevented tumor growth in resistant CRPC models both in monotherapy (0.5 mg/kg) and in enzalutamide-combination therapy. Mechanistic study revealed that by targeting importin-β1, DD1-Br markedly inhibited the nuclear accumulation of multiple CRPC drivers, particularly AR-V7, a main contributor to enzalutamide resistance, leading to the integral suppression of downstream oncogenic signaling. This study provides a promising lead for CRPC and demonstrates the potential of overcoming drug resistance in advanced CRPC via targeting importin-β1. |
| first_indexed | 2024-03-09T15:40:54Z |
| format | Article |
| id | doaj.art-6fc49276dc944b37a9e55038536ea213 |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-03-09T15:40:54Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-6fc49276dc944b37a9e55038536ea2132023-11-25T04:47:43ZengElsevierActa Pharmaceutica Sinica B2211-38352023-12-01131249344944Discovery of a highly potent and orally available importin-β1 inhibitor that overcomes enzalutamide-resistance in advanced prostate cancerJia-Luo Huang0Xue-Long Yan1Dong Huang2Lu Gan3Huahua Gao4Run-Zhu Fan5Shen Li6Fang-Yu Yuan7Xinying Zhu8Gui-Hua Tang9Hong-Wu Chen10Junjian Wang11Sheng Yin12School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; School of Pharmacy, Guizhou Medical University, Guian New District, Guizhou 550025, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaSchool of Medicine, University of California Davis, Sacramento, CA 95817, USASchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; Corresponding authors.School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; Corresponding authors.Nuclear transporter importin-β1 is emerging as an attractive target by virtue of its prevalence in many cancers. However, the lack of druggable inhibitors restricts its therapeutic proof of concept. In the present work, we optimized a natural importin-β1 inhibitor DD1 to afford an improved analog DD1-Br with better tolerability (>25 folds) and oral bioavailability. DD1-Br inhibited the survival of castration-resistant prostate cancer (CRPC) cells with sub-nanomolar potency and completely prevented tumor growth in resistant CRPC models both in monotherapy (0.5 mg/kg) and in enzalutamide-combination therapy. Mechanistic study revealed that by targeting importin-β1, DD1-Br markedly inhibited the nuclear accumulation of multiple CRPC drivers, particularly AR-V7, a main contributor to enzalutamide resistance, leading to the integral suppression of downstream oncogenic signaling. This study provides a promising lead for CRPC and demonstrates the potential of overcoming drug resistance in advanced CRPC via targeting importin-β1.http://www.sciencedirect.com/science/article/pii/S2211383523002794Importin-β1CRPCDrug discoveryEnzalutamide-resistanceNatural productCancer |
| spellingShingle | Jia-Luo Huang Xue-Long Yan Dong Huang Lu Gan Huahua Gao Run-Zhu Fan Shen Li Fang-Yu Yuan Xinying Zhu Gui-Hua Tang Hong-Wu Chen Junjian Wang Sheng Yin Discovery of a highly potent and orally available importin-β1 inhibitor that overcomes enzalutamide-resistance in advanced prostate cancer Acta Pharmaceutica Sinica B Importin-β1 CRPC Drug discovery Enzalutamide-resistance Natural product Cancer |
| title | Discovery of a highly potent and orally available importin-β1 inhibitor that overcomes enzalutamide-resistance in advanced prostate cancer |
| title_full | Discovery of a highly potent and orally available importin-β1 inhibitor that overcomes enzalutamide-resistance in advanced prostate cancer |
| title_fullStr | Discovery of a highly potent and orally available importin-β1 inhibitor that overcomes enzalutamide-resistance in advanced prostate cancer |
| title_full_unstemmed | Discovery of a highly potent and orally available importin-β1 inhibitor that overcomes enzalutamide-resistance in advanced prostate cancer |
| title_short | Discovery of a highly potent and orally available importin-β1 inhibitor that overcomes enzalutamide-resistance in advanced prostate cancer |
| title_sort | discovery of a highly potent and orally available importin β1 inhibitor that overcomes enzalutamide resistance in advanced prostate cancer |
| topic | Importin-β1 CRPC Drug discovery Enzalutamide-resistance Natural product Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211383523002794 |
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