Science 368, 1386–1392 (2020)

Cellular condensates are membraneless organelles that compartmentalize biomolecules. In particular, the nucleus contains a number of condensates, defined by molecular markers such as MED1 and BRD4 for transcriptional condensates, that are sufficient on their own to produce droplets. To test whether small molecules also selectively concentrate in particular condensates, Klein et. al tested the effects of fluorescently labeled cisplatin and tamoxifen on different nuclear condensates. Both compounds concentrated specifically in MED1 condensates while diffusing easily through other condensates. Analysis of a library of fluorescent compounds revealed that π–π or π–cation interactions facilitated entry into MED1 condensates by interaction with aromatic residues in MED1. Accumulation of cisplatin in MED1 condensates resulted in increased target engagement, and disruption of the MED1 condensate by BRD4 inhibition reduced the effect of cisplatin. Overall, the findings of Klein et al. will enable the rational design of small-molecule therapeutics to target specific nuclear condensates.

Credit: Alessandra Dall’Agnese