Parallel Automated Flow Synthesis of Covalent Protein Complexes That Can Inhibit MYC-Driven Transcription
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acscentsci.1c00663.pdf
Description
Published version
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6.45 MB
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Author(s)
Pomplun, Sebastian
Jbara, Muhammad
Schissel, Carly K
Wilson Hawken, Susana
Boija, Ann
Li, Charles
Klein, Isaac
Pentelute, Bradley L
Date Issued
2021
Journal
ACS Central Science
Publisher
American Chemical Society (ACS)
Citation
Pomplun, Sebastian, Jbara, Muhammad, Schissel, Carly K, Wilson Hawken, Susana, Boija, Ann et al. 2021. "Parallel Automated Flow Synthesis of Covalent Protein Complexes That Can Inhibit MYC-Driven Transcription." ACS Central Science, 7 (8).
Version
Final published version
Abstract
Dysregulation of the transcription factor MYC is involved in many human cancers. The dimeric transcription factor complexes of MYC/MAX and MAX/MAX activate or inhibit, respectively, gene transcription upon binding to the same enhancer box DNA. Targeting these complexes in cancer is a long-standing challenge. Inspired by the inhibitory activity of the MAX/MAX dimer, we engineered covalently linked, synthetic homo- and heterodimeric protein complexes to attenuate oncogenic MYC-driven transcription. We prepared the covalent protein complexes (∼20 kDa, 167-231 residues) in a single shot via parallel automated flow synthesis in hours. The stabilized covalent dimers display DNA binding activity, are intrinsically cell-penetrant, and inhibit cancer cell proliferation in different cell lines. RNA sequencing and gene set enrichment analysis in A549 cancer cells confirmed that the synthetic dimers interfere with MYC-driven transcription. Our results demonstrate the potential of automated flow technology to rapidly deliver engineered synthetic protein complex mimetics that can serve as a starting point in developing inhibitors of MYC-driven cancer cell growth.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
Massachusetts Institute of Technology. Center for Environmental Health Sciences
Koch Institute for Integrative Cancer Research at MIT
Whitehead Institute for Biomedical Research
Massachusetts Institute of Technology. Department of Biology
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1021/ACSCENTSCI.1C00663
