2. Academic Validation
  3. EGFR targeting PhosTACs as a dual inhibitory approach reveals differential downstream signaling

EGFR targeting PhosTACs as a dual inhibitory approach reveals differential downstream signaling

  • Sci Adv. 2024 Mar 29;10(13):eadj7251. doi: 10.1126/sciadv.adj7251.
Zhenyi Hu 1 2,  Po-Han Chen 1 3 4,  Wenxue Li 5,  Mackenzie Krone 1,  Sijin Zheng 1,  Jacques Saarbach 1,  Ines Urquizo Velasco 1,  John Hines 1,  Yansheng Liu 5,  Craig M Crews 1 6 7 8
Affiliations

Affiliations

  • 1 Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA.
  • 2 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China.
  • 3 Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan City, 701, Taiwan.
  • 4 Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan City, 701, Taiwan.
  • 5 Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, USA.
  • 6 Department of Chemistry, Yale University, New Haven, CT 06511, USA.
  • 7 Department of Pharmacology, Yale University, New Haven, CT 06511, USA.
  • 8 Yale University School of Medicine, New Haven, CT 06511, USA.
PMID: 38536914 DOI: 10.1126/sciadv.adj7251
Abstract

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.

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