Academic Journal
EGFR targeting PhosTACs as a dual inhibitory approach reveals differential downstream signaling
| العنوان: | EGFR targeting PhosTACs as a dual inhibitory approach reveals differential downstream signaling |
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| المؤلفون: | Hu, Zhenyi, Chen, Po-Han, Li, Wenxue, Krone, Mackenzie, Zheng, Sijin, Saarbach, Jacques, Velasco, Ines Urquizo, Hines, John, Liu, Yansheng, Crews, Craig M. |
| المصدر: | Science Advances ; volume 10, issue 13 ; ISSN 2375-2548 |
| بيانات النشر: | American Association for the Advancement of Science (AAAS) |
| سنة النشر: | 2024 |
| الوصف: | We recently developed a heterobifunctional approach [phosphorylation targeting chimeras (PhosTACs)] to achieve the targeted protein dephosphorylation (TPDephos). Here, we envisioned combining the inhibitory effects of receptor tyrosine kinase inhibitors (RTKIs) and the active dephosphorylation by phosphatases to achieve dual inhibition of kinases. We report an example of tyrosine phosphatase–based TPDephos and the effective epidermal growth factor receptor (EGFR) tyrosine dephosphorylation. We also used phosphoproteomic approaches to study the signaling transductions affected by PhosTAC-related molecules at the proteome-wide level. This work demonstrated the differential signaling pathways inhibited by PhosTAC compared with the TKI, gefitinib. Moreover, a covalent PhosTAC selective for mutated EGFR was developed and showed its inhibitory potential for dysregulated EGFR. Last, EGFR PhosTACs, consistent with EGFR dephosphorylation profiles, induced apoptosis and inhibited cancer cell viability during prolonged PhosTAC treatment. PhosTACs showcased their potential of modulating RTKs activity, expanding the scope of bifunctional molecule utility. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1126/sciadv.adj7251 |
| الاتاحة: | http://dx.doi.org/10.1126/sciadv.adj7251 https://www.science.org/doi/pdf/10.1126/sciadv.adj7251 |
| رقم الانضمام: | edsbas.4896BBD9 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1126/sciadv.adj7251 |
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