The FGFR inhibitor PD173074 binds to the C-terminus of oncofetal HMGA2 and modulates its DNA-binding and transcriptional activation functions
The architectural chromatin factor high-mobility group AT-hook 2 (HMGA2) is causally involved in several human malignancies and pathologies. HMGA2 is not expressed in most normal adult somatic cells, which renders the protein an attractive drug target. An established cell-based compound library scre...
| Main Authors: | , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
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2023
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| Online Access: | https://hdl.handle.net/10356/169924 |
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| author | Ahmed, Syed Moiz Ragunathan, Priya Shin, Joon Peter, Sabrina Kleissle, Sabrina Neuenschwander, Martin Schäfer, Reinhold Kries, Jens Peter V. Grüber, Gerhard Dröge, Peter |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Ahmed, Syed Moiz Ragunathan, Priya Shin, Joon Peter, Sabrina Kleissle, Sabrina Neuenschwander, Martin Schäfer, Reinhold Kries, Jens Peter V. Grüber, Gerhard Dröge, Peter |
| author_sort | Ahmed, Syed Moiz |
| collection | NTU |
| description | The architectural chromatin factor high-mobility group AT-hook 2 (HMGA2) is causally involved in several human malignancies and pathologies. HMGA2 is not expressed in most normal adult somatic cells, which renders the protein an attractive drug target. An established cell-based compound library screen identified the fibroblast growth factor receptor (FGFR) inhibitor PD173074 as an antagonist of HMGA2-mediated transcriptional reporter gene activation. We determined that PD173074 binds the C-terminus of HMGA2 and interferes with functional coordination of the three AT-hook DNA-binding domains mediated by the C-terminus. The HMGA2-antagonistic effect of PD173074 on transcriptional activation may therefore result from an induced altered DNA-binding mode of HMGA2. PD173074 as a novel HMGA2-specific antagonist could trigger the development of derivates with enhanced attributes and clinical potential. |
| first_indexed | 2025-02-19T03:08:10Z |
| format | Journal Article |
| id | ntu-10356/169924 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2025-02-19T03:08:10Z |
| publishDate | 2023 |
| record_format | dspace |
| spelling | ntu-10356/1699242023-08-15T03:04:10Z The FGFR inhibitor PD173074 binds to the C-terminus of oncofetal HMGA2 and modulates its DNA-binding and transcriptional activation functions Ahmed, Syed Moiz Ragunathan, Priya Shin, Joon Peter, Sabrina Kleissle, Sabrina Neuenschwander, Martin Schäfer, Reinhold Kries, Jens Peter V. Grüber, Gerhard Dröge, Peter School of Biological Sciences Science::Biological sciences AT-hook Domain C-terminal Domain The architectural chromatin factor high-mobility group AT-hook 2 (HMGA2) is causally involved in several human malignancies and pathologies. HMGA2 is not expressed in most normal adult somatic cells, which renders the protein an attractive drug target. An established cell-based compound library screen identified the fibroblast growth factor receptor (FGFR) inhibitor PD173074 as an antagonist of HMGA2-mediated transcriptional reporter gene activation. We determined that PD173074 binds the C-terminus of HMGA2 and interferes with functional coordination of the three AT-hook DNA-binding domains mediated by the C-terminus. The HMGA2-antagonistic effect of PD173074 on transcriptional activation may therefore result from an induced altered DNA-binding mode of HMGA2. PD173074 as a novel HMGA2-specific antagonist could trigger the development of derivates with enhanced attributes and clinical potential. This work was funded by the Ministry of Education Academic Research Fund Tier 3 (MOE2012-T3-1-001to PD) and by the National Research Foundation(NRF) Singapore, Competitive Research Programme(CRP), Grant Award Number NRF-CRP18-2017-01(GG). We acknowledge support by the German Cancer Consortium (DKTK) to RS. 2023-08-15T03:04:10Z 2023-08-15T03:04:10Z 2023 Journal Article Ahmed, S. M., Ragunathan, P., Shin, J., Peter, S., Kleissle, S., Neuenschwander, M., Schäfer, R., Kries, J. P. V., Grüber, G. & Dröge, P. (2023). The FGFR inhibitor PD173074 binds to the C-terminus of oncofetal HMGA2 and modulates its DNA-binding and transcriptional activation functions. FEBS Letters, 597(15), 1977-1988. https://dx.doi.org/10.1002/1873-3468.14675 0014-5793 https://hdl.handle.net/10356/169924 10.1002/1873-3468.14675 37259564 2-s2.0-85161723890 15 597 1977 1988 en MOE2012-T3-1-001 RF-CRP18-2017-01 FEBS Letters © 2023 Federation of European Biochemical Societies. All rights reserved. |
| spellingShingle | Science::Biological sciences AT-hook Domain C-terminal Domain Ahmed, Syed Moiz Ragunathan, Priya Shin, Joon Peter, Sabrina Kleissle, Sabrina Neuenschwander, Martin Schäfer, Reinhold Kries, Jens Peter V. Grüber, Gerhard Dröge, Peter The FGFR inhibitor PD173074 binds to the C-terminus of oncofetal HMGA2 and modulates its DNA-binding and transcriptional activation functions |
| title | The FGFR inhibitor PD173074 binds to the C-terminus of oncofetal HMGA2 and modulates its DNA-binding and transcriptional activation functions |
| title_full | The FGFR inhibitor PD173074 binds to the C-terminus of oncofetal HMGA2 and modulates its DNA-binding and transcriptional activation functions |
| title_fullStr | The FGFR inhibitor PD173074 binds to the C-terminus of oncofetal HMGA2 and modulates its DNA-binding and transcriptional activation functions |
| title_full_unstemmed | The FGFR inhibitor PD173074 binds to the C-terminus of oncofetal HMGA2 and modulates its DNA-binding and transcriptional activation functions |
| title_short | The FGFR inhibitor PD173074 binds to the C-terminus of oncofetal HMGA2 and modulates its DNA-binding and transcriptional activation functions |
| title_sort | fgfr inhibitor pd173074 binds to the c terminus of oncofetal hmga2 and modulates its dna binding and transcriptional activation functions |
| topic | Science::Biological sciences AT-hook Domain C-terminal Domain |
| url | https://hdl.handle.net/10356/169924 |
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