Discovery of a phase-separating small molecule that selectively sequesters tubulin in cells
Genyir Ado, Naotaka Noda, Huệ Thị Vũ, Amélie Perron, Amarjyoti Das Mahapatra, Karla Pineda Arista, Hideaki Yoshimura, Daniel M. Packwood, Fumiyoshi Ishidate, Shin‐ichi Sato, Takeaki Ozawa, Motonari Uesugi
Abstract
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.