Bridged Proteolysis Targeting Chimera (PROTAC) Enables Degradation of Undruggable Targets

Abstract

Proteolysis Targeting Chimeras (PROTACs) are attractive therapeutic modalities for degrading disease-causing proteins. While many PROTACs have been developed for numerous protein targets, current small-molecule PROTAC approaches cannot target undruggable proteins that do not have small-molecule binders. Here, we present a novel PROTAC approach, termed bridged PROTAC, which utilizes a small-molecule binder of the target protein’s binding partner to recruit the protein complex into close proximity with an E3 ubiquitin ligase to target undruggable proteins. Applying this bridged PROTAC strategy, we discovered MS28, the first-in-class degrader of cyclin D1, which lacks a small-molecule binder. MS28 effectively degrades cyclin D1, with faster degradation kinetics and superior degradation efficiency than CDK4/6, through recruiting the CDK4/6-cyclin D1 complex to the von Hippel–Lindau E3 ligase. MS28 also suppressed the proliferation of cancer cells more effectively than CDK4/6 inhibitors and degraders. Altogether, the bridged PROTAC strategy could provide a generalizable platform for targeting undruggable proteins.

Targeted protein posttranslational modifications by chemically induced proximity for cancer therapy

“…Additionally, CDK inhibitors CR8 ( 41 ), HQ461 ( 42 ), and dCeMM ( 43 ) degrade Cyclin K in cells by recruiting the CDK12/Cyclin K complex onto the DDB1-CUL4-RBX1 E3 ligase, suggesting that TPD may also be initiated by a bridging protein that forms a stable complex with the target protein. Moreover, a bridge PROTAC MS28 has been developed to degrade Cyclin D1 by conjugating the VHL ligand to a ligand of CDK4/6, stable binding partner proteins of Cyclin D1 ( 54 ). As a result, MS28 effectively degrades both cyclin D1 and CDK4/6 in a VHL-dependent manner, making it more potent than CDK4/6 inhibitors and degraders ( 54 ).…”

“…Moreover, a bridge PROTAC MS28 has been developed to degrade Cyclin D1 by conjugating the VHL ligand to a ligand of CDK4/6, stable binding partner proteins of Cyclin D1 ( 54 ). As a result, MS28 effectively degrades both cyclin D1 and CDK4/6 in a VHL-dependent manner, making it more potent than CDK4/6 inhibitors and degraders ( 54 ). The studies suggest that it is possible to transform undruggable proteins into druggable targets through the utilization of POI binding proteins as bait and bridge during PROTAC development.…”

Discovery of LL-K8-22: A Selective, Durable, and Small-Molecule Degrader of the CDK8-Cyclin C Complex

“…Moreover, degraders can also interfere with the function of the protein complex and even degrade the undruggable targets. 30 Thus, pharmacological intervention of the CDK8−cyclin C complex by target protein degradation approaches may provide more profound antitumor effects than CDK8 kinase inhibitors, and direct effects on cyclin C activity would help to reveal the uncharacterized functions of cyclin C in tumor development. So far, two CDK8 degraders have been reported.…”

“…A recent study also showed that the bridged PROTAC approach enables degradation of undruggable targets, such as cyclin D1. 30 Inspired by these discoveries, we further explored whether HyT could achieve degradation of the CDK8−cyclin C complex, especially the non-druggable protein cyclin C. Here, we describe the development of the CDK8−cyclin C dual degrader, LL-K8-22, whose parental compound is a potent CDK8/19 inhibitor BI-1347. 38 LL-K8-22 is also the first-in-class degrader of cyclin C. Biological evaluation identified that LL-K8-22 triggered synchronous, selective, and durable degradation of CDK8 and cyclin C in triplenegative breast cancer (TNBC) cells.…”

“…It has been shown that small-molecule degraders can improve selectivity in the dimension of protein stability and thus may decrease off-target effects. Moreover, degraders can also interfere with the function of the protein complex and even degrade the undruggable targets . Thus, pharmacological intervention of the CDK8–cyclin C complex by target protein degradation approaches may provide more profound anti-tumor effects than CDK8 kinase inhibitors, and direct effects on cyclin C activity would help to reveal the uncharacterized functions of cyclin C in tumor development.…”