New-generation advanced PROTACs as potential therapeutic agents in cancer therapy

Abstract

Proteolysis-targeting chimeras (PROTACs) technology has garnered significant attention over the last 10 years, representing a burgeoning therapeutic approach with the potential to address pathogenic proteins that have historically posed challenges for traditional small-molecule inhibitors. PROTACs exploit the endogenous E3 ubiquitin ligases to facilitate degradation of the proteins of interest (POIs) through the ubiquitin-proteasome system (UPS) in a cyclic catalytic manner. Despite recent endeavors to advance the utilization of PROTACs in clinical settings, the majority of PROTACs fail to progress beyond the preclinical phase of drug development. There are multiple factors impeding the market entry of PROTACs, with the insufficiently precise degradation of favorable POIs standing out as one of the most formidable obstacles. Recently, there has been exploration of new-generation advanced PROTACs, including small-molecule PROTAC prodrugs, biomacromolecule-PROTAC conjugates, and nano-PROTACs, to improve the in vivo efficacy of PROTACs. These improved PROTACs possess the capability to mitigate undesirable physicochemical characteristics inherent in traditional PROTACs, thereby enhancing their targetability and reducing off-target side effects. The new-generation of advanced PROTACs will mark a pivotal turning point in the realm of targeted protein degradation. In this comprehensive review, we have meticulously summarized the state-of-the-art advancements achieved by these cutting-edge PROTACs, elucidated their underlying design principles, deliberated upon the prevailing challenges encountered, and provided an insightful outlook on future prospects within this burgeoning field.

Keywords: Cancer therapy; Nanomedicine; New-generation PROTACs; Precise protein degradation; Prodrug.

Fig. 1

Timeline of PROTAC discoveries (adapted from [3])

Fig. 2

The development history of PROTACs. A The total number of PROTAC publications and the part of that about cancer each year (web of science core collection). B Percent of PROTACs in different disease fields which are in preclinical phase (web of science core collection)

Fig. 3

A PROTAC-mediated degradation of target proteins through the UPS; B The tenets of PROTAC targets

Fig. 4

The typical shortcomings of PROTACs

Fig. 5

Overview of strategies utilized in the advanced PROTAC design

Fig. 6

A Cartoon showing the structure of the click-release PROTAC prodrugs. B Chemical structures of the click-release PROTAC prodrugs (adapted from [49, 50]). C Chemical structures of the click-release PROTAC prodrug (adapted from [51]). D Chemical structures of the click-release PROTAC prodrugs (adapted from [52]). E Chemical structures of the click-release PROTAC prodrug (adapted from [53])

Fig. 7

A Cartoon showing the structure of the folate-targeting PROTAC prodrugs. B Chemical structures of the folate-targeting PROTAC prodrugs (adapted from [57]). C Chemical structures of the folate-targeting PROTAC prodrug (adapted from [58])

Fig. 8

A Cartoon showing the structure of the photo-caged PROTAC prodrugs. B Chemical structures of the photo-caged PROTAC prodrugs (adapted from [64]). C Chemical structures of the photo-caged PROTAC prodrugs (adapted from [65]). D Chemical structures of the photo-caged PROTAC prodrugs (adapted from [66]). E Chemical structures of the photo-caged PROTAC prodrug (adapted from [67])

Fig. 9

A Cartoon showing the structure of the photo-switchable PROTAC prodrugs (adapted from [68]). B Chemical structures of the photo-switchable PROTAC prodrugs (adapted from [68]). C Chemical structures of the photo-switchable PROTAC prodrugs (adapted from [69]). D Chemical structures of the photo-switchable PROTAC prodrugs (adapted from [70]). E Chemical structures of the photo-switchable PROTAC prodrugs (adapted from [71])

Fig. 10

A Cartoon showing the structure of the radiation-responsive PROTAC prodrugs (adapted from [68]). B Chemical structures of the radiation-responsive PROTAC (adapted from [76]). C Chemical structures of the radiation-responsive PROTAC (adapted from [77])

Fig. 11

A Cartoon showing the structure of the enzyme-responsive PROTAC prodrugs (adapted from [68]). B Chemical structures of the enzyme-responsive PROTAC (adapted from [81]). C Chemical structures of the enzyme-responsive PROTAC (adapted from [81]). D Chemical structures of the enzyme-responsive PROTAC (adapted from [82]). E Chemical structures of the enzyme-responsive PROTAC (adapted from [77])

Fig. 12

A Cartoon showing the structure of the GSH-responsive PROTAC prodrugs (adapted from [68]). B Chemical structures of the GSH-responsive PROTAC prodrug (adapted from [93])

Fig. 13

A Cartoon showing the structure of the hypoxia-responsive PROTAC prodrugs (adapted from [68]). B Chemical structures of the hypoxia-responsive PROTACs (adapted from [97]). C Chemical structures of the hypoxia-responsive PROTAC (adapted from [98]). D Chemical structures of the hypoxia-responsive PROTAC (adapted from [99]). E Chemical structures of the hypoxia-responsive PROTACs (adapted from [100]). F Chemical structures of the hypoxia-responsive PROTAC (adapted from [101])

Fig. 14

A Cartoon showing the structure of the ROS-responsive PROTAC prodrug (adapted from [68]). B Chemical structures of the ROS-responsive PROTAC prodrug (adapted from [105]). C Chemical structures of the ROS-responsive PROTAC prodrugs (adapted from [106])

Fig. 15

A Cartoon showing the structure of the antibody-PROTAC conjugates (adapted from [68]). B Chemical structures of the antibody-PROTAC conjugate (adapted from [112]). C Chemical structures of the antibody-PROTAC conjugate (adapted from [113]). D Chemical structures of the antibody-PROTAC conjugate (adapted from [114]). E Chemical structures of the antibody-PROTAC conjugates (adapted from [115]). F Chemical structures of the antibody-PROTAC conjugate (adapted from [116]). G Chemical structures of the antibody-PROTAC conjugates (adapted from [117]). H Chemical structures of the antibody-PROTAC conjugates (adapted from [118])

Fig. 16

A Cartoon showing the structure of the aptamer-PROTAC conjugates (adapted from [68]). B Chemical structures of the antibody-PROTAC conjugate (adapted from [123]). C Chemical structures of the antibody-PROTAC conjugate (adapted from [124]). D Chemical structures of the antibody-PROTAC conjugate (adapted from [125]). E Chemical structures of the antibody-PROTAC conjugate (adapted from [126])

Fig. 17

A Cartoon showing the structure of the nano-PROTAC polymers (adapted from [68]). B Chemical structures of the structure of the nano-PROTACs (adapted from [135]). C Chemical structures of the structure of the nano-PROTACs (adapted from [136, 137]). D Chemical structures of the structure of the nano-PROTACs (adapted from [138]). E Chemical structures of the structure of the nano-PROTACs (adapted from [139]). F Chemical structures of the structure of the nano-PROTACs (adapted from [140]). G Chemical structures of the structure of the nano-PROTACs (adapted from [141]). H Chemical structures of the structure of the nano-PROTACs (adapted from [142]). I Chemical structures of the structure of the nano-PROTACs (adapted from [143]). J Chemical structures of the structure of the nano-PROTACs (adapted from [144]). K Chemical structures of the structure of the nano-PROTACs (adapted from [145]). L Chemical structures of the structure of the nano-PROTACs (adapted from [146]). M Chemical structures of the structure of the nano-PROTACs (adapted from [147]). N Chemical structures of the structure of the nano-PROTACs (adapted from [148])