Bifunctional chemical probes inducing protein–protein interactions

Abstract

Stabilizing biomolecular interactions with synthetic molecules to impact biological function is a concept of enormous appeal. Although much effort has been devoted to disrupting proteinprotein interactions (PPIs) using inhibitors, less attention has been directed toward the reverse strategy, that of inducing new PPIs. However recent years have seen a resurgence of interest in designing molecules that bring proteins together. This approach promises to significantly expand the range of tractable targets for chemical biology and therapeutic intervention. Pioneering structural and biophysical investigation of ternary complexes formed by mono-and bifunctional ligands highlight that proximity-induced stabilization or de novo formation of PPIs are a common feature of their molecular recognition. In this review, we illustrate these concepts and advances with representative case studies, and highlight progress over the past three years, with particular focus on recruitment to E3 ubiquitin ligases by "molecular glues" and chimeric dimerizers (PROTACs) for targeted protein degradation.

Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation

“…As a result, molecular glues have been viewed enthusiastically as a unique pharmacological modality to target proteins without druggable pockets (Maniaci & Ciulli, 2019).…”

Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders

“…14,15,19,20 The eld of proteolysis targeting chimeras (PROTACs) has made tremendous achievements and reached substantial milestones in the last years. [21][22][23][24][25][26][27][28][29] Briey, PROTACs are bifunctional small molecules, which comprise two linker-connected moieties that simultaneously bind a target protein and an E3 ubiquitin ligase. Frequently employed E3 ligase binders 3-6 which have successfully been utilized in PROTAC design are presented in Fig.…”

Improved Accuracy for Modeling PROTAC-Mediated Ternary Complex Formation and Targeted Protein Degradation via NewIn SilicoMethodologies

“…46,47 Although it seems that the ternary complex need not be particularly stable or long-lived for target degradation to occur, 48,49 it is becoming increasingly apparent that "cooperativity" -where formation of the three-body complex is favored over formation of either binary complex -is beneficial for effective protein degradation. 50,51 It is thus expected -and indeed is borne out by the validation data (see below) -that the methods of this work should prove especially successful at modeling these more stable ternary complexes.…”