Structure-based discovery of potent WD repeat domain 5 inhibitors that demonstrate efficacy and safety in preclinical animal models
| العنوان: | Structure-based discovery of potent WD repeat domain 5 inhibitors that demonstrate efficacy and safety in preclinical animal models |
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| المؤلفون: | Kevin B. Teuscher, Somenath Chowdhury, Kenneth M. Meyers, Jianhua Tian, Jiqing Sai, Mayme Van Meveren, Taylor M. South, John L. Sensintaffar, Tyson A. Rietz, Soumita Goswami, Jing Wang, Brian C. Grieb, Shelly L. Lorey, Gregory C. Howard, Qi Liu, William J. Moore, Gordon M. Stott, William P. Tansey, Taekyu Lee, Stephen W. Fesik |
| المصدر: | Proceedings of the National Academy of Sciences. 120 |
| بيانات النشر: | Proceedings of the National Academy of Sciences, 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Mice, WD40 Repeats, Multidisciplinary, Neoplasms, Cell Line, Tumor, Models, Animal, Intracellular Signaling Peptides and Proteins, Animals, Humans, Chromatin |
| الوصف: | WD repeat domain 5 (WDR5) is a core scaffolding component of many multiprotein complexes that perform a variety of critical chromatin-centric processes in the nucleus. WDR5 is a component of the mixed lineage leukemia MLL/SET complex and localizes MYC to chromatin at tumor-critical target genes. As a part of these complexes, WDR5 plays a role in sustaining oncogenesis in a variety of human cancers that are often associated with poor prognoses. Thus, WDR5 has been recognized as an attractive therapeutic target for treating both solid and hematological tumors. Previously, small-molecule inhibitors of the WDR5-interaction (WIN) site and WDR5 degraders have demonstrated robust in vitro cellular efficacy in cancer cell lines and established the therapeutic potential of WDR5. However, these agents have not demonstrated significant in vivo efficacy at pharmacologically relevant doses by oral administration in animal disease models. We have discovered WDR5 WIN-site inhibitors that feature bicyclic heteroaryl P 7 units through structure-based design and address the limitations of our previous series of small-molecule inhibitors. Importantly, our lead compounds exhibit enhanced on-target potency, excellent oral pharmacokinetic (PK) profiles, and potent dose-dependent in vivo efficacy in a mouse MV4:11 subcutaneous xenograft model by oral dosing. Furthermore, these in vivo probes show excellent tolerability under a repeated high-dose regimen in rodents to demonstrate the safety of the WDR5 WIN-site inhibition mechanism. Collectively, our results provide strong support for WDR5 WIN-site inhibitors to be utilized as potential anticancer therapeutics. |
| تدمد: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.2211297120 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f55525b23552d424473dfa053dbc6302 https://doi.org/10.1073/pnas.2211297120 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....f55525b23552d424473dfa053dbc6302 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
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| DOI: | 10.1073/pnas.2211297120 |