PROteolysis TArgetting Chimeras (PROTACs) Strategy Applied to Kinases: Recent Advances

Abstract

Since the development of the first protein kinase inhibitor in the early 1980s, followed by the FDA approval of imatinib in 2001, kinases are one of the most intensively pursued targets in current medicinal chemistry research. These proteins are overrepresented in various diseases such as cancer, inflammation or autoimmune pathologies and play important roles in their physiopathogenic processes. Despite the development and approval of numerous potent kinase inhibitors, drug resistance and off‐target side effects are commonly encountered with kinase inhibitors. Thus, development of novel strategies to overcome these problems is necessary. Since 2013, many research groups have proposed the conversion of potent kinase inhibitors into PROteolysis TArgeting Chimera (PROTAC) compounds and shared relevant and encouraging results using this new technology, which degrades proteins by employing the cellular machinery. Generally, this strategy brings enhancements in biological effects compared to the use of only the parent inhibitor. In this review article, recent findings related to the PROTAC technology applied to kinases are discussed, with a special focus on publications since 2018.

Advances in Strategies and Tools Available for Interrogation of Protein O‐GlcNAcylation

“…A chemical knockdown strategy [114] referred to as proteolysis targeting chimeras (PROTACs) has been developed to reduce specific protein levels as an alternative to genetic knockdown approaches such as antisense oligonucleotides, RNA interference (RNAi) or CRISPER‐Cas 9 strategies. The PROTACs strategy hijacks the cellular proteostasis apparatus to degrade a specific protein target using a PROTAC molecule [115,116] . PROTAC molecules have two functional moieties connected by a linker, one moiety recruiting an E3 ubiquitin ligase, the other moiety binding the target, leading to a ternary complex formation.…”

“…Then the E3 ligase recruited by the PROTACs molecule ubiquitinates the target protein and the resulting polyubiquitinated protein is subjected to degradation by the proteasome (Figure 12A). A number of small PROTAC molecules satisfying cell permeability and greater metabolic stability have been reported to induce the destruction of specified protein targets [115,117–119] . In the PROTAC mechanism, the PROTAC molecules are regenerated after they finish their duty of inducing target degradation, acting like a catalyst.…”

Development of an N-Terminal BRD4 Bromodomain-Targeted Degrader

“…Targeted degraders co-opt cellular proteostasis machinery, inducing proximity between cellular E3 protein-ubiquitin ligases (E3) and proteins of interest, resulting in proteasomal degradation of target proteins. Given their substoichiometric mode of action, modularity in design, and promise of targeting traditionally “undruggable” targets, degraders have been reported for a wide variety of protein classes including BET proteins. − BET-degraders have improved therapeutic efficacy compared to BET-inhibition alone, but both face challenges with dose-limiting toxicities including thrombocytopenia attributed in part to targeting BRD2 and BRD3 . While selective degraders have been developed from promiscuous ligands, including selective BRD4-degraders from pan-BET inhibitors (Figure ), − the design elements for achieving selectivity remains a nontrivial endeavor.…”

Development of an N-Terminal BRD4 Bromodomain-Targeted Degrader

“…Given their sub-stoichiometric mode of action, modularity in design and promise of targeting traditionally 'undruggable' targets, degraders have been reported for a wide variety of protein classes including BET proteins. [11][12][13] BET-degraders have improved therapeutic efficacy compared to BET-inhibition alone, 14 but both face challenges with dose-limiting toxicities including thrombocytopenia attributed to targeting BRD2 and BRD3. 15 While selective degraders have been developed from promiscuous ligands, 16 including selective BRD4-degraders from pan-BET inhibitors (Figure 1), [17][18][19] the design of selectivity remains a non-trivial endeavor.…”