Small-molecule PROTACs: An emerging and promising approach for the development of targeted therapy drugs

Abstract

There are several challenges towards the development and clinical use of small molecule inhibitors, which are currently the main type of targeted therapies towards intracellular proteins. PROteolysis-TArgeting Chimeras (PROTACs) exploit the intracellular ubiquitin-proteasome system to selectively degrade target proteins. Recently, small-molecule PROTACs with high potency have been frequently reported. In this review, we summarize the emerging characteristics of small-molecule PROTACs, such as inducing a rapid, profound and sustained degradation, inducing a robust inhibition of downstream signals, displaying enhanced target selectivity, and overcoming resistance to small molecule inhibitors. In tumor xenografts, small-molecule PROTACs can significantly attenuate tumor progression. In addition, we also introduce recent developments of the PROTAC technology such as homo-PROTACs. The outstanding advantages over traditional small-molecule drugs and the promising preclinical data suggest that small-molecule PROTAC technology has the potential to greatly promote the development of targeted therapy drugs.

Keywords: E3 ligases; Induced protein degradation; PROTAC; Targeted therapy drugs; Ubiquitin-proteasome system.

Fig. 1

Overview of the mechanisms of small molecule inhibitors and PROTACs (a) In order to inhibit the activities of target proteins, small molecule inhibitors competitively bind to active sites on the target proteins. The limitations on developing and taking small molecule drugs are shown in this figure. (b) Heterobifunctional PROTAC molecules harness the ubiquitin proteasome system to selectively degrade target proteins. Currently, the generation of PROTACs relies on available small molecular inhibitors to be used as target binding ligands. Alternatively, PROTACs can bind to any crevice on the surface of the target proteins to induce their degradation.

Fig. 2

Characteristics of PROTACs (a) Protein-protein interactions (PPIs) between the target protein and the E3 ligase can stabilize the target:PROTAC:E3 complex even when the affinity between the target and the PROTAC is weak. The formation of stable ternary complexes is required for the induced protein degradation. (b) A hook effect shows when the systemic concentration of PROTACs is too high. High concentrations of dimeric PROTAC:E3 and PROTAC:target complexes inhibit the formation of degradation-inducing ternary complexes.

Fig. 3

Other modalities of PROTACs (a) Homo-PROTACs are bivalent small-molecules that can trigger the dimerization of an E3 ligase and its subsequent self-degradation. (b) In contrast to typical PROTACs, general PROTACs cross-link E3 ligases and tagged fusion proteins and subsequently degrade fusion proteins. General PROTACs can be flexibly utilized to degrade variable proteins and study the functions of particular proteins. (c) Through bio-orthogonal click combination of two tagged small molecule precursors, heterobifunctional PROTACs can be formed intracellularly and successfully induce the degradation of target proteins. This approach was created to overcome the high molecular weight nature of typical PROTACs which contain two small-molecule ligands and a linker.