Molecular glues for protein-protein interactions: Progressing toward a new dream

Markella Konstantinidou; Michelle R Arkin

doi:10.1016/j.chembiol.2024.04.002

Molecular glues for protein-protein interactions: Progressing toward a new dream

Cell Chem Biol. 2024 Apr 25:S2451-9456(24)00130-2. doi: 10.1016/j.chembiol.2024.04.002. Online ahead of print.

Authors

Markella Konstantinidou¹, Michelle R Arkin²

Affiliations

¹ Department of Pharmaceutical Chemistry and Small Molecule Discovery Center (SMDC), University of California, San Francisco, San Francisco, CA 94143, USA.
² Department of Pharmaceutical Chemistry and Small Molecule Discovery Center (SMDC), University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: michelle.arkin@ucsf.edu.

PMID: 38701786
DOI: 10.1016/j.chembiol.2024.04.002

Abstract

The modulation of protein-protein interactions with small molecules is one of the most rapidly developing areas in drug discovery. In this review, we discuss advances over the past decade (2014-2023) focusing on molecular glues (MGs)-monovalent small molecules that induce proximity, either by stabilizing native interactions or by inducing neomorphic interactions. We include both serendipitous and rational discoveries and describe the different approaches that were used to identify them. We classify the compounds in three main categories: degradative MGs, non-degradative MGs or PPI stabilizers, and MGs that induce self-association. Diverse, illustrative examples with structural data are described in detail, emphasizing the elements of molecular recognition and cooperative binding at the interface that are fundamental for a MG mechanism of action.

Keywords: PPI; cooperativity; covalent; degraders; molecular glues; molecular recognition; native interactions; neomorphic; proximity; stabilizers; ternary complex.

Publication types

Review