Partitioning of Cancer Therapeutics in Nuclear Condensates

Overview

Journal Science

Specialty Science

Date 2020 Jun 20

PMID 32554597

Citations 212

Authors

Isaac A Klein

Ann Boija

Lena K Afeyan

Susana Wilson Hawken

Mengyang Fan

Alessandra DallAgnese

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

Affiliations

Soon will be listed here.

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.

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