Discovery of a phase-separating small molecule that selectively sequesters tubulin in cells

• Published in: Chemical science (Cambridge) Vol. 13; no. 19; pp. 576 - 5766
• Main Authors: Ado, Genyir, Noda, Naotaka, Vu, Hue T, Perron, Amelie, Mahapatra, Amarjyoti D, Arista, Karla Pineda, Yoshimura, Hideaki, Packwood, Daniel M, Ishidate, Fumiyoshi, Sato, Shin-ichi, Ozawa, Takeaki, Uesugi, Motonari
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 18-05-2022; The Royal Society of Chemistry
• Subjects: Cellular structure; Chemistry; Condensates; Feasibility studies; Mitosis; Modular structures; Organelles; Organic chemistry; Self-assembly
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/d1sc07151c

Phase-separated membraneless organelles or biomolecular condensates play diverse functions in cells, however recapturing their characteristics using small organic molecules has been a challenge. In the present study, cell-lysate-based screening of 843 self-assembling small molecules led to the discovery of a simple organic molecule, named huezole, that forms liquid droplets to selectively sequester tubulin. Remarkably, this small molecule enters cultured human cells and prevents cell mitosis by forming tubulin-concentrating condensates in cells. The present study demonstrates the feasibility of producing a synthetic condensate out of non-peptidic small molecules for exogenous control of cellular processes. The modular structure of huezole provides a framework for designing a class of organelle-emulating small molecules.
A non-peptidic small molecule,
R
-huezole, phase separates to selectively sequester tubulin proteins to control the cell cycle. Its modular structure provides a framework for designing bioactive molecules to mimic membraneless organelles in cells.