Partitioning of cancer therapeutics in nuclear condensates

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

doi:10.1126/science.aaz4427

Partitioning of cancer therapeutics in nuclear condensates

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. HannettYang 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

Research output: Contribution to journal › Article › peer-review

249 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1386-1392
Number of pages	7
Journal	Science
Volume	368
Issue number	6497
DOIs	https://doi.org/10.1126/science.aaz4427
State	Published - Jun 19 2020
Externally published	Yes

ASJC Scopus subject areas

General

Access to Document

10.1126/science.aaz4427

Cite this

Klein, I. A., Boija, A., Afeyan, L. K., Hawken, S. W., Fan, M., Dall'Agnese, A., Oksuz, O., Henninger, J. E., Shrinivas, K., Sabari, B. R., Sagi, I., Clark, V. E., Platt, J. M., Kar, M., McCall, P. M., Zamudio, A. V., Manteiga, J. C., Coffey, E. L., Li, C. H., ... Young, R. A. (2020). Partitioning of cancer therapeutics in nuclear condensates. Science, 368(6497), 1386-1392. https://doi.org/10.1126/science.aaz4427

Klein, IA, Boija, A, Afeyan, LK, Hawken, SW, Fan, M, Dall'Agnese, A, Oksuz, O, Henninger, JE, Shrinivas, K, Sabari, BR, Sagi, I, Clark, VE, Platt, JM, Kar, M, McCall, PM, Zamudio, AV, Manteiga, JC, Coffey, EL, Li, CH, Hannett, NM, Guo, YE, Decker, TM, Lee, TI, Zhang, T, Weng, JK, Taatjes, DJ, Chakraborty, A, Sharp, PA, Chang, YT, Hyman, AA, Gray, NS & Young, RA 2020, 'Partitioning of cancer therapeutics in nuclear condensates', Science, vol. 368, no. 6497, pp. 1386-1392. https://doi.org/10.1126/science.aaz4427

@article{9a67c209fdd043d89c3b373909015063,

title = "Partitioning of cancer therapeutics in nuclear condensates",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works",

year = "2020",

month = jun,

day = "19",

doi = "10.1126/science.aaz4427",

language = "English (US)",

volume = "368",

pages = "1386--1392",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6497",

}

TY - JOUR

T1 - Partitioning of cancer therapeutics in nuclear condensates

AU - Klein, Isaac A.

AU - Boija, Ann

AU - Afeyan, Lena K.

AU - Hawken, Susana Wilson

AU - Fan, Mengyang

AU - Dall'Agnese, Alessandra

AU - Oksuz, Ozgur

AU - Henninger, Jonathan E.

AU - Shrinivas, Krishna

AU - Sabari, Benjamin R.

AU - Sagi, Ido

AU - Clark, Victoria E.

AU - Platt, Jesse M.

AU - Kar, Mrityunjoy

AU - McCall, Patrick M.

AU - Zamudio, Alicia V.

AU - Manteiga, John C.

AU - Coffey, Eliot L.

AU - Li, Charles H.

AU - Hannett, Nancy M.

AU - Guo, Yang Eric

AU - Decker, Tim Michael

AU - Lee, Tong Ihn

AU - Zhang, Tinghu

AU - Weng, Jing Ke

AU - Taatjes, Dylan J.

AU - Chakraborty, Arup

AU - Sharp, Phillip A.

AU - Chang, Young Tae

AU - Hyman, Anthony A.

AU - Gray, Nathanael S.

AU - Young, Richard A.

PY - 2020/6/19

Y1 - 2020/6/19

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85086725637&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85086725637&partnerID=8YFLogxK

U2 - 10.1126/science.aaz4427

DO - 10.1126/science.aaz4427

M3 - Article

C2 - 32554597

AN - SCOPUS:85086725637

SN - 0036-8075

VL - 368

SP - 1386

EP - 1392

JO - Science

JF - Science

IS - 6497

ER -

Partitioning of cancer therapeutics in nuclear condensates

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this