Developing novel Lin28 inhibitors by computer aided drug design
Abstract Lin28 is a key regulator of cancer stem cell gene network that promotes therapy-resistant tumor progression in various tumors. However, no Lin28 inhibitor has been approved to treat cancer patients, urging exploration of novel compounds as candidates to be tested for clinical trials. In thi...
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| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-01-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-024-02281-z |
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| author | Victor M. Matias-Barrios Mariia Radaeva Graciella Rosellinny Qiongqiong Jia Ning Xie Monica Villanueva Hanadi Ibrahim Jason Smith Martin Gleave Nada Lallous Suzana K. Straus Artem Cherkasov Xuesen Dong |
| author_facet | Victor M. Matias-Barrios Mariia Radaeva Graciella Rosellinny Qiongqiong Jia Ning Xie Monica Villanueva Hanadi Ibrahim Jason Smith Martin Gleave Nada Lallous Suzana K. Straus Artem Cherkasov Xuesen Dong |
| author_sort | Victor M. Matias-Barrios |
| collection | DOAJ |
| description | Abstract Lin28 is a key regulator of cancer stem cell gene network that promotes therapy-resistant tumor progression in various tumors. However, no Lin28 inhibitor has been approved to treat cancer patients, urging exploration of novel compounds as candidates to be tested for clinical trials. In this contribution, we applied computer-aided drug design (CADD) in combination with quantitative biochemical and biological assays. These efforts led to the discovery of Ln268 as a drug candidate that can block Lin28 from binding to its RNA substrates and inhibit Lin28 activities. Ln268 suppressed Lin28-mediated cancer cell proliferation and spheroid growth. Results from nuclear magnetic resonance spectroscopy confirmed that Ln268 perturbs the conformation of the zinc knuckle domain of Lin28, validating the rational drug design by CADD. The inhibitory effects of Ln268 are dependent on Lin28 protein expression in cancer cells, highlighting limited off-target effects of Ln268. Moreover, Ln268 synergizes with several chemotherapy drugs to suppress tumor cell growth. In summary, Ln268 is a promising candidate for further development to target Lin28 as a cancer therapy. |
| format | Article |
| id | doaj-art-ce63f0f37758428997db4f24716a5778 |
| institution | Kabale University |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-ce63f0f37758428997db4f24716a57782025-01-12T12:08:15ZengNature Publishing GroupCell Death Discovery2058-77162025-01-0111111110.1038/s41420-024-02281-zDeveloping novel Lin28 inhibitors by computer aided drug designVictor M. Matias-Barrios0Mariia Radaeva1Graciella Rosellinny2Qiongqiong Jia3Ning Xie4Monica Villanueva5Hanadi Ibrahim6Jason Smith7Martin Gleave8Nada Lallous9Suzana K. Straus10Artem Cherkasov11Xuesen Dong12The Vancouver Prostate Centre, Department of Urologic Sciences, University of British ColumbiaThe Vancouver Prostate Centre, Department of Urologic Sciences, University of British ColumbiaThe Vancouver Prostate Centre, Department of Urologic Sciences, University of British ColumbiaThe Vancouver Prostate Centre, Department of Urologic Sciences, University of British ColumbiaThe Vancouver Prostate Centre, Department of Urologic Sciences, University of British ColumbiaDepartment of Chemistry, University of British ColumbiaThe Vancouver Prostate Centre, Department of Urologic Sciences, University of British ColumbiaThe Vancouver Prostate Centre, Department of Urologic Sciences, University of British ColumbiaThe Vancouver Prostate Centre, Department of Urologic Sciences, University of British ColumbiaThe Vancouver Prostate Centre, Department of Urologic Sciences, University of British ColumbiaDepartment of Chemistry, University of British ColumbiaThe Vancouver Prostate Centre, Department of Urologic Sciences, University of British ColumbiaThe Vancouver Prostate Centre, Department of Urologic Sciences, University of British ColumbiaAbstract Lin28 is a key regulator of cancer stem cell gene network that promotes therapy-resistant tumor progression in various tumors. However, no Lin28 inhibitor has been approved to treat cancer patients, urging exploration of novel compounds as candidates to be tested for clinical trials. In this contribution, we applied computer-aided drug design (CADD) in combination with quantitative biochemical and biological assays. These efforts led to the discovery of Ln268 as a drug candidate that can block Lin28 from binding to its RNA substrates and inhibit Lin28 activities. Ln268 suppressed Lin28-mediated cancer cell proliferation and spheroid growth. Results from nuclear magnetic resonance spectroscopy confirmed that Ln268 perturbs the conformation of the zinc knuckle domain of Lin28, validating the rational drug design by CADD. The inhibitory effects of Ln268 are dependent on Lin28 protein expression in cancer cells, highlighting limited off-target effects of Ln268. Moreover, Ln268 synergizes with several chemotherapy drugs to suppress tumor cell growth. In summary, Ln268 is a promising candidate for further development to target Lin28 as a cancer therapy.https://doi.org/10.1038/s41420-024-02281-z |
| spellingShingle | Victor M. Matias-Barrios Mariia Radaeva Graciella Rosellinny Qiongqiong Jia Ning Xie Monica Villanueva Hanadi Ibrahim Jason Smith Martin Gleave Nada Lallous Suzana K. Straus Artem Cherkasov Xuesen Dong Developing novel Lin28 inhibitors by computer aided drug design Cell Death Discovery |
| title | Developing novel Lin28 inhibitors by computer aided drug design |
| title_full | Developing novel Lin28 inhibitors by computer aided drug design |
| title_fullStr | Developing novel Lin28 inhibitors by computer aided drug design |
| title_full_unstemmed | Developing novel Lin28 inhibitors by computer aided drug design |
| title_short | Developing novel Lin28 inhibitors by computer aided drug design |
| title_sort | developing novel lin28 inhibitors by computer aided drug design |
| url | https://doi.org/10.1038/s41420-024-02281-z |
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