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Partitioning of cancer therapeutics in nuclear condensates.

Science (New York, N.Y.) (2020-06-20)
Isaac A Klein, Ann Boija, Lena K Afeyan, Susana Wilson Hawken, Mengyang Fan, Alessandra Dall'Agnese, Ozgur Oksuz, Jonathan E Henninger, Krishna Shrinivas, Benjamin R Sabari, Ido Sagi, Victoria E Clark, Jesse M Platt, Mrityunjoy Kar, Patrick M McCall, Alicia V Zamudio, John C Manteiga, Eliot L Coffey, Charles H Li, Nancy M Hannett, Yang Eric Guo, Tim-Michael Decker, Tong Ihn Lee, Tinghu Zhang, Jing-Ke Weng, Dylan J Taatjes, Arup Chakraborty, Phillip A Sharp, Young Tae Chang, Anthony A Hyman, Nathanael S Gray, Richard A Young
PMID32554597
ABSTRACT

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.