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Engineering Bioactive Dimeric Transcription Factor Analogs via Palladium Rebound Reagents
Muhammad Jbara1, Sebastian Pomplun1, Carly K Schissel1
1Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
Journal of the American Chemical Society
|July 22, 2021
Summary
Synthetic protein dimers targeting oncogenic Myc transcription factors were engineered. The covalent Max-Max dimer inhibits cancer cell proliferation by interfering with Myc-dependent gene transcription.
Area of Science:
- Biochemistry
- Molecular Biology
- Medicinal Chemistry
Background:
- Myc is a transcription factor (TF) implicated in 50% of human cancers.
- Targeting Myc is challenging due to its lack of small molecule binding pockets.
Purpose of the Study:
- To engineer synthetic covalently linked TF mimetics that inhibit oncogenic Myc-driven transcription.
- To develop a practical strategy for generating new bioactive compounds to inhibit tumor cell proliferation.
Main Methods:
- Automated flow peptide chemistry combined with palladium(II) oxidative addition complexes (OACs).
- Engineering covalent protein dimers from Myc, Max, and Omomyc TF analogs.
- Palladium-mediated cross-coupling to generate homo- and heterodimers.
Main Results:
- Seven different covalent homo- and heterodimers were synthesized in milligram quantities.
- Covalent helical dimers bind DNA and show improved thermal stability.
- The Max-Max covalent dimer is cell-penetrating, inhibits Myc-dependent transcription, and reduces cancer cell proliferation (EC50 of 6 μM in HeLa).
Conclusions:
- Flow chemistry and palladium(II) OACs provide a practical strategy for generating novel bioactive compounds.
- Covalent Max-Max homodimer effectively interferes with Myc-dependent transcription, offering a potential therapeutic strategy against Myc-driven cancers.
