Partitioning of cancer therapeutics in nuclear condensates
Name
nihms-1647011.pdf
Description
Accepted version
Size
1.96 MB
Format
Unknown
Checksum (MD5)
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Author(s)
Klein, Isaac A.
Boija, Ann
Afeyan, Lena K.
Hawken, Susana Wilson
Fan, Mengyang
Dall'Agnese, Alessandra
Oksuz, Ozgur
Henninger, Jonathan E.
Shrinivas, Krishna
Sabari, Benjamin R.
Date Issued
June 2020
Journal
Science
Publisher
American Association for the Advancement of Science (AAAS)
Version
Author's final manuscript
Abstract
© 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works The nucleus contains diverse phase-separated condensates that compartmentalize and concentrate biomolecules with distinct physicochemical properties. Here, we investigated whether condensates concentrate small-molecule cancer therapeutics such that their pharmacodynamic properties are altered. We found that antineoplastic drugs become concentrated in specific protein condensates in vitro and that this occurs through physicochemical properties independent of the drug target. This behavior was also observed in tumor cells, where drug partitioning influenced drug activity. Altering the properties of the condensate was found to affect the concentration and activity of drugs. These results suggest that selective partitioning and concentration of small molecules within condensates contributes to drug pharmacodynamics and that further understanding of this phenomenon may facilitate advances in disease therapy.
MIT Department
Whitehead Institute for Biomedical Research
Massachusetts Institute of Technology. Department of Physics
Massachusetts Institute of Technology. Department of Chemical Engineering
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Massachusetts Institute of Technology. Department of Chemistry
Massachusetts Institute of Technology. Department of Biological Engineering
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1126/science.aaz4427
