Partitioning of cancer therapeutics in nuclear condensates

Author:

Klein Isaac A.12ORCID,Boija Ann1ORCID,Afeyan Lena K.13,Hawken Susana Wilson13,Fan Mengyang45ORCID,Dall'Agnese Alessandra1ORCID,Oksuz Ozgur1ORCID,Henninger Jonathan E.1ORCID,Shrinivas Krishna67ORCID,Sabari Benjamin R.1ORCID,Sagi Ido1ORCID,Clark Victoria E.18ORCID,Platt Jesse M.19,Kar Mrityunjoy10ORCID,McCall Patrick M.101112ORCID,Zamudio Alicia V.13,Manteiga John C.13ORCID,Coffey Eliot L.13,Li Charles H.13ORCID,Hannett Nancy M.1,Guo Yang Eric1,Decker Tim-Michael13ORCID,Lee Tong Ihn1ORCID,Zhang Tinghu45,Weng Jing-Ke13ORCID,Taatjes Dylan J.13,Chakraborty Arup67141516ORCID,Sharp Phillip A.317ORCID,Chang Young Tae18ORCID,Hyman Anthony A.1119ORCID,Gray Nathanael S.45ORCID,Young Richard A.13ORCID

Affiliation:

1. Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.

2. Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.

3. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

4. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

5. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

6. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

7. Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

8. Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

9. Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.

10. Max Planck Institute for the Physics of Complex Systems, 01187 Dresden, Germany.

11. Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.

12. Center for Systems Biology Dresden, 01307 Dresden, Germany.

13. Department of Biochemistry, University of Colorado, Boulder, CO 80303, USA.

14. Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

15. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

16. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

17. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

18. Department of Chemistry, Pohang University of Science and Technology, and Center for Self-assembly and Complexity, Institute for Basic Science (IBS), Pohang 37673, Republic of Korea.

19. Cluster of Excellence Physics of Life, Technical University of Dresden, 01062 Dresden, Germany.

Abstract

Drug partitioning in nuclear condensates There is increasing interest in the function of phase-separated biomolecular condensates in cells because of their distinct properties and expanding roles in important biological processes. Klein et al. considered the fate of small-molecule therapeutics in the context of nuclear condensates (see the Perspective by Viny and Levine). They show that certain antineoplastic drugs have physicochemical properties that cause them to concentrate preferentially in condensates, both in vitro and in cancer cells. This property influences drug activity, and protein mutations that alter condensate formation can lead to drug resistance. Optimizing condensate partitioning may be valuable in developing improved therapeutics. Science , this issue p. 1386 ; see also p. 1314

Funder

National Science Foundation

National Institutes of Health

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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