Intrinsically disordered regions (IDRs) in proteins are increasingly recognized as attractive targets for therapeutic intervention. A number of small molecules interacting with IDRs have been identified, but the lack of persistent secondary and tertiary structure of these regions has led to the prevailing view that they cannot be targeted selectively. Here, we show that a small molecule targeting an IDR evaluated in a clinical trial interacts selectively with an oligomeric form of its target, which is more structured than the monomer and is stabilized by interactions involving aromatic residues in partially α-helical regions. The interaction reshapes the conformational ensemble of the target, alters the biophysical properties of its phase-separated condensates in vitro, and attenuates RNA polymerase II recruitment in cells. Our findings provide mechanistic insights into how small molecules can selectively recognize IDRs.
Bielskutė et al. (Fri,) studied this question.