Extrapolating Lessons from Targeted Protein Degradation to Other Proximity-Inducing Drugs

Abstract

Targeted protein degradation (TPD) is an emerging pharmacologic strategy. It relies on small-molecule "degraders" that induce proximity of a component of an E3 ubiquitin ligase complex and a target protein to induce target ubiquitination and subsequent proteasomal degradation. Essentially, degraders thus expand the function of E3 ligases, allowing them to degrade proteins they would not recognize in the absence of the small molecule. Over the past decade, insights gained from identifying, designing, and characterizing various degraders have significantly enhanced our understanding of TPD mechanisms, precipitating in rational degrader discovery strategies. In this Account, I aim to explore how these insights can be extrapolated to anticipate both opportunities and challenges of utilizing the overarching concept of proximity-inducing pharmacology to manipulate other cellular circuits for the dissection of biological mechanisms and for therapeutic purposes.

Figure 1

Proximity-inducing pharmacology via chemical neomorphs. (A) General logic of a chemical neomorph that binds to a protein of interest (POI), chemically rewires its surface properties to install or stabilize a novel protein–protein interaction. (B) High level description of how changes in the POI interactome can theoretically manifest in different POI fates and activities.

Figure 2

Two main classes of small-molecule degraders. Schematic comparison of key characteristics of heterobifunctional degraders (PROTACs, including trivalent PROTACs) that act in trans and molecular glue degraders (MGDs, including intramolecular bivalent glue degraders) that act in cis. MGDs typically only engage one protein: the POI or the E3/effector. Pre-existing affinity relates to affinities between POI and effector.

Figure 3

Degraders facilitate a mechanistic understanding. (A) Directly acting and genetically encoded small-molecule degraders typically operate within a few hours and thus at a different time scale than most genetic perturbations. (B) Through this higher kinetic resolution, degraders can help to identify primary mechanistic consequences and approximate causality in biological systems.

Figure 4

Unique characteristics of degrader-induced ternary complexes. (A) Schematic display of how effector processivity dictates the requirement for a stable ternary complex. (B) Other effector characteristics that influence success of proximity-inducing pharmacology. Schematically displayed are the requirements for a particular amino acid motif, the size of the sampled protein surface of the POI, as well as the variability of the outcome of a given posttranslational modification.

Figure 5

Relevance of the “point of no return” for the success of targeted protein degradation. (A) Schematic depiction of the interplay between E3/DUB in POI (de)ubiquitination and the point of no return that occurs when the poly ubiquitinated POI gets degraded by the proteasome. (B) The point of no return facilitates effective catalysis that is elicited by the degrader. This causes an extended duration of the functional effect (C) and puts less emphasis on favorable stoichiometry between POI and effector (D).