Small molecule PROTACs: an emerging technology for targeted therapy in drug discovery

Abstract

Curing malignant carcinomas is a grand ambition in the development of human health. Over the past decades, targeted therapies have become one of the most successful ways of achieving this. Of these approaches, small molecule inhibitors and monoclonal antibodies are two major methods, however several barriers to their development and clinical use still exist. The use of proteolysis-targeting chimeras (PROTACs) is a new technology through utilizing a intracellular ubiquitin-proteasome system to induce targeted protein degradation, is receiving much attention in the field of targeted therapies. Hetero-bifunctional PROTACs have the potential to eliminate the "undruggable" proteome that comprises about 85% of human proteins, which indicates their great prospects in therapeutic fields. However, there are some hurdles preventing current PROTACs moving from bench to clinic, such as delivery and bioavailability. This review provides an overview of the development of PROTAC technology and will briefly summarize the future possible directions of this approach.

Fig. 1. The degradation cycle of an E3 ligase using PROTACs. The blue oval represents the protein of interest (POI) and the orange oval represents the E3 ligase for recruiting. A PROTAC molecule comprises a warhead to target the POI, an E3 ligand to recruit the E3 ligase and a linker to connect them. When the PROTAC molecule draws the POI and E3 ligase close, E3 will employ an E2 ubiquitin-conjugating enzyme to transfer ubiquitin to the surface of the targeted protein. Then the proteasome will recognize the polyubiquitination signal and degrade the POI. At the same time, the PROTAC molecule will separate from the ternary complex and participate in another degradation cycle.

Fig. 2. A graph showing the publications associated with PROTAC technology. Data from Web of Science (http://apps.webofknowledge.com). This graph reflects the number of articles and reviews. As can be seen, a drastic increase from 2014 indicates the rapid development of PROTAC technology.

Fig. 3. An MDM2-based PROTAC (AR targeting).

Fig. 4. (a) A cIAP-based PROTAC (CRABPII targeting), and (b) XIAP-based PROTAC (ER targeting).

Fig. 5. CRBN-based PROTACs: (a) dBET1 (BRD4-targeting); (b) ARV-825 (BRD4-targeting); and (c) P13I (BTK-targeting).

Fig. 6. VHL-based PROTACs: (a) PROTAC_ERRα (ERRα-targeting); (b) PROTAC_RIPK2 (RIPK2-targeting); (c) ARV-771 (BRD4-targeting); and (d) MZ1/MZ2 (BRD4-targeting).

Fig. 7. (a) The structures of JQ1-TCO and Tz-thalidomide. (b) The mechanism of CLIPTACs. Two precursor molecules penetrate the cytomembrane in succession and form a CLIPTAC intracellularly, resulting in the proteasome degradation of BRD4.

Fig. 8. A schematic diagram showing a HaloPROTAC. The HaloPTORAC utilizes the specific recognition by HaloTag7 of hexyl chloride tags and thus induces the degradation of HaloTag7-GFP fused proteins. This strategy simplifies the optimization of PROTACs.