Academic Journal
Structure-Based Discovery of Potent, Orally Bioavailable Benzoxazepinone-Based WD Repeat Domain 5 Inhibitors
| العنوان: | Structure-Based Discovery of Potent, Orally Bioavailable Benzoxazepinone-Based WD Repeat Domain 5 Inhibitors |
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| المؤلفون: | Kevin B. Teuscher, Jonathan J. Mills, Jianhua Tian, Changho Han, Kenneth M. Meyers, Jiqing Sai, Taylor M. South, Mackenzie M. Crow, Mayme Van Meveren, John L. Sensintaffar, Bin Zhao, Kangsa Amporndanai, William J. Moore, Gordon M. Stott, William P. Tansey, Taekyu Lee, Stephen W. Fesik |
| سنة النشر: | 2023 |
| مصطلحات موضوعية: | Biochemistry, Genetics, Pharmacology, Biotechnology, Evolutionary Biology, Cancer, Hematology, Environmental Sciences not elsewhere classified, Biological Sciences not elsewhere classified, Chemical Sciences not elsewhere classified, ray structural analysis, 5 ( 2, associated protein wdr5, >)- one core, advanced wdr5 win, study opens avenues, orally bioavailable benzoxazepinone, cancer drug discovery, 4 ] oxazepin, based wdr5 win, 7 , potent wdr5 inhibitors, wdr5 win, based discovery, site inhibitors, cancer therapeutics, bicyclic core, h <, f <, based counterparts |
| الوصف: | The chromatin-associated protein WDR5 (WD repeat domain 5) is an essential cofactor for MYC and a conserved regulator of ribosome protein gene transcription. It is also a high-profile target for anti-cancer drug discovery, with proposed utility against both solid and hematological malignancies. We have previously discovered potent dihydroisoquinolinone-based WDR5 WIN-site inhibitors with demonstrated efficacy and safety in animal models. In this study, we sought to optimize the bicyclic core to discover a novel series of WDR5 WIN-site inhibitors with improved potency and physicochemical properties. We identified the 3,4-dihydrobenzo[ f ][1,4]oxazepin-5(2 H )-one core as an alternative scaffold for potent WDR5 inhibitors. Additionally, we used X-ray structural analysis to design partially saturated bicyclic P 7 units. These benzoxazepinone-based inhibitors exhibited increased cellular potency and selectivity and favorable physicochemical properties compared to our best-in-class dihydroisoquinolinone-based counterparts. This study opens avenues to discover more advanced WDR5 WIN-site inhibitors and supports their development as novel anti-cancer therapeutics. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | unknown |
| Relation: | https://figshare.com/articles/journal_contribution/Structure-Based_Discovery_of_Potent_Orally_Bioavailable_Benzoxazepinone-Based_WD_Repeat_Domain_5_Inhibitors/24795038 |
| DOI: | 10.1021/acs.jmedchem.3c01529.s001 |
| الاتاحة: | https://doi.org/10.1021/acs.jmedchem.3c01529.s001 https://figshare.com/articles/journal_contribution/Structure-Based_Discovery_of_Potent_Orally_Bioavailable_Benzoxazepinone-Based_WD_Repeat_Domain_5_Inhibitors/24795038 |
| Rights: | CC BY-NC 4.0 |
| رقم الانضمام: | edsbas.7EB7FCFE |
| قاعدة البيانات: | BASE |
| DOI: | 10.1021/acs.jmedchem.3c01529.s001 |
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