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Oligomerization enables the selective targeting of intrinsically disordered regions by small molecules

par Stasė Bielskutė, Borja Mateos, Muhammad Awawdy, Carla Garcia-Cabau, Henri Niskanen, Carolina Sánchez-Zarzalejo, Lorenzo Bracaglia, Roberta Pierattelli, Isabella C. Felli, Marta Frigolé-Vivas, Jesús García, Antoni Riera, Denes Hnisz et Xavier Salvatella

Publié: 22 mars 2025
Serveur de preprints: bioRxiv
DOI: 10.1101/2025.03.21.644603

Résumé

Intrinsically disordered regions (IDRs) are challenging drug targets because they lack stable interaction sites for drug-like molecules. We studied the first small molecule targeting an IDR to be evaluated in a clinical trial and found that it interacts selectively with an oligomeric form of the protein, more structured than the monomeric state, that is stabilized by interactions involving aromatic residues in regions with helical propensity. We also found that this compound alters the network of interactions defining the conformational ensemble of its target, thus affecting its condensation properties, linked to its function as a transcription factor. These findings provide a framework for developing strategies to target intrinsically disordered regions with small molecules.

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PREreview par Nikhil Gupta et al.

Rédigé par Nikhil Gupta, James Fraser et 2 autres auteurs

Review for: Oligomerization enables the selective targeting of intrinsically disordered regions by small molecules.

https://www.biorxiv.org/content/10.1101/2025.03.21.644603v1.full
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