Partitioning of cancer therapeutics in nuclear condensates,Science

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Partitioning of cancer therapeutics in nuclear condensates
Science ( IF 56.9 ) Pub Date : 2020-06-18 , DOI: 10.1126/science.aaz4427
Isaac A Klein _{1,

2} , Ann Boija ₁ , Lena K Afeyan _{1,

3} , Susana Wilson Hawken _{1,

3} , Mengyang Fan _{4,

5} , Alessandra Dall'Agnese ₁ , Ozgur Oksuz ₁ , Jonathan E Henninger ₁ , Krishna Shrinivas _{6,

7} , Benjamin R Sabari ₁ , Ido Sagi ₁ , Victoria E Clark _{1,

8} , Jesse M Platt _{1,

9} , Mrityunjoy Kar ₁₀ , Patrick M McCall _{10,

11,

12} , Alicia V Zamudio _{1,

3} , John C Manteiga _{1,

3} , Eliot L Coffey _{1,

3} , Charles H Li _{1,

3} , Nancy M Hannett ₁ , Yang Eric Guo ₁ , Tim-Michael Decker ₁₃ , Tong Ihn Lee ₁ , Tinghu Zhang _{4,

5} , Jing-Ke Weng _{1,

3} , Dylan J Taatjes ₁₃ , Arup Chakraborty _{6,

7,

14,

15,

16,

17,

18} , Phillip A Sharp _{3,

18} , Young Tae Chang ₁₉ , Anthony A Hyman _{11,

20} , Nathanael S Gray _{4,

5} , Richard A Young ₁

Affiliation

Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
Max Planck Institute for the Physics of Complex Systems, 01187 Dresden, Germany.
Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
Center for Systems Biology Dresden, 01307 Dresden, Germany.
Department of Biochemistry, University of Colorado, Boulder, CO 80303, USA.
Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard Medical School, Cambridge, MA 02139, USA.
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
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.
Cluster of Excellence Physics of Life, Technical University of Dresden, 01062 Dresden, Germany.

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 Phase-separated condensates in the cell nucleus concentrate small-molecule drugs, modulating their on-target activity and pharmacodynamics. 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.

中文翻译：

核凝聚物中癌症治疗剂的分配

核凝聚物中的药物分配由于相分离的生物分子凝聚物在重要生物过程中的独特特性和扩展作用，它们在细胞中的功能越来越受到关注。克莱因等人。考虑了在核凝聚物的背景下小分子疗法的命运（见 Viny 和 Levine 的观点）。他们表明，某些抗肿瘤药物具有物理化学特性，导致它们在体外和癌细胞中优先浓缩在凝聚物中。这种特性会影响药物活性，改变凝聚物形成的蛋白质突变会导致耐药性。优化冷凝分配可能对开发改进的治疗方法很有价值。科学，这个问题 p。第1386章另见第。细胞核中的 1314 相分离冷凝物浓缩小分子药物，调节其靶向活性和药效学。细胞核包含不同的相分离冷凝物，可分隔和浓缩具有不同物理化学特性的生物分子。在这里，我们研究了凝聚物是否浓缩了小分子癌症治疗剂，从而改变了它们的药效学特性。我们发现抗肿瘤药物在体外集中在特定的蛋白质缩合物中，这是通过独立于药物靶点的物理化学特性发生的。在肿瘤细胞中也观察到这种行为，其中药物分配影响药物活性。发现改变冷凝物的性质会影响药物的浓度和活性。

更新日期：2020-06-18

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