In situ inhibitor synthesis and screening by fluorescence polarization: an efficient approach for accelerating drug discovery
Target-directed dynamic combinatorial chemistry has emerged as a useful tool for hit identification, but has not been widely used, in part due to challenges associated with analyses involving complex mixtures. We describe an operationally simple alternative: in situ inhibitor synthesis and screening...
| Main Authors: | , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Wiley
2022
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| _version_ | 1797110580958461952 |
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| author | Li, Z Wu, Y Zhen, S Su, K Zhang, L Yang, F McDonough, MA Schofield, CJ Zhang, X |
| author_facet | Li, Z Wu, Y Zhen, S Su, K Zhang, L Yang, F McDonough, MA Schofield, CJ Zhang, X |
| author_sort | Li, Z |
| collection | OXFORD |
| description | Target-directed dynamic combinatorial chemistry has emerged as a useful tool for hit identification, but has not been widely used, in part due to challenges associated with analyses involving complex mixtures. We describe an operationally simple alternative: in situ inhibitor synthesis and screening (ISISS), which links high-throughput bioorthogonal synthesis with screening for target binding by fluorescence. We exemplify the ISISS method by showing how coupling screening for target binding by fluorescence polarization with the reaction of acyl-hydrazides and aldehydes led to the efficient discovery of a potent and novel acylhydrazone-based inhibitor of human prolyl hydroxylase 2 (PHD2), a target for anemia treatment, with equivalent in vivo potency to an approved medicine. |
| first_indexed | 2024-03-07T07:56:48Z |
| format | Journal article |
| id | oxford-uuid:f5a711fe-adc7-448c-8375-7a3643cb7be0 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:56:48Z |
| publishDate | 2022 |
| publisher | Wiley |
| record_format | dspace |
| spelling | oxford-uuid:f5a711fe-adc7-448c-8375-7a3643cb7be02023-08-22T12:55:00ZIn situ inhibitor synthesis and screening by fluorescence polarization: an efficient approach for accelerating drug discoveryJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:f5a711fe-adc7-448c-8375-7a3643cb7be0EnglishSymplectic ElementsWiley2022Li, ZWu, YZhen, SSu, KZhang, LYang, FMcDonough, MASchofield, CJZhang, XTarget-directed dynamic combinatorial chemistry has emerged as a useful tool for hit identification, but has not been widely used, in part due to challenges associated with analyses involving complex mixtures. We describe an operationally simple alternative: in situ inhibitor synthesis and screening (ISISS), which links high-throughput bioorthogonal synthesis with screening for target binding by fluorescence. We exemplify the ISISS method by showing how coupling screening for target binding by fluorescence polarization with the reaction of acyl-hydrazides and aldehydes led to the efficient discovery of a potent and novel acylhydrazone-based inhibitor of human prolyl hydroxylase 2 (PHD2), a target for anemia treatment, with equivalent in vivo potency to an approved medicine. |
| spellingShingle | Li, Z Wu, Y Zhen, S Su, K Zhang, L Yang, F McDonough, MA Schofield, CJ Zhang, X In situ inhibitor synthesis and screening by fluorescence polarization: an efficient approach for accelerating drug discovery |
| title | In situ inhibitor synthesis and screening by fluorescence polarization: an efficient approach for accelerating drug discovery |
| title_full | In situ inhibitor synthesis and screening by fluorescence polarization: an efficient approach for accelerating drug discovery |
| title_fullStr | In situ inhibitor synthesis and screening by fluorescence polarization: an efficient approach for accelerating drug discovery |
| title_full_unstemmed | In situ inhibitor synthesis and screening by fluorescence polarization: an efficient approach for accelerating drug discovery |
| title_short | In situ inhibitor synthesis and screening by fluorescence polarization: an efficient approach for accelerating drug discovery |
| title_sort | in situ inhibitor synthesis and screening by fluorescence polarization an efficient approach for accelerating drug discovery |
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