Disordered region of cereblon is required for efficient degradation by proteolysis-targeting chimera

Kim, Kidae; Lee, Dong Hoon; Park, Sungryul; Jo, Seunghyun; Ku, Bonsu; Park, Sung Goo; Park, Byoung Chul; Jeon, Yeong Uk; Ahn, Sunjoo; Kang, Chung Hyo; Hwang, Daehee; Chae, Sehyun; Ha, Jae Du; Kim, Sunhong; Hwang, Jong Yeon; Kim, Jeong-Hoon

doi:10.1038/s41598-019-56177-5

Cited by 29 publications

(21 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4C ). 52 All three groups developed PROTAC degraders of slightly different chemical structures, yet in all cases preferential degradation of CRBN was observed, suggesting that the homo-PROTAC approach could be used to hijack E3 ligases against each other for inducing selective E3 ligase degradation.…”

Section: Introductionmentioning

confidence: 95%

See 1 more Smart Citation

E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones

2021

View full text Add to dashboard Cite

Bifunctional degrader molecules, also called proteolysis-targeting chimeras (PROTACs), are a new modality of chemical tools and potential therapeutics to understand and treat human disease. A required PROTAC component is a ligand binding to an E3 ubiquitin ligase, which is then joined to another ligand binding to a protein to be degraded via the ubiquitin–proteasome system. The advent of nonpeptidic small-molecule E3 ligase ligands, notably for von Hippel–Lindau (VHL) and cereblon (CRBN), revolutionized the field and ushered in the design of drug-like PROTACs with potent and selective degradation activity. A first wave of PROTAC drugs are now undergoing clinical development in cancer, and the field is seeking to extend the repertoire of chemistries that allow hijacking new E3 ligases to improve the scope of targeted protein degradation. Here, we briefly review how traditional E3 ligase ligands were discovered, and then outline approaches and ligands that have been recently used to discover new E3 ligases for PROTACs. We will then take an outlook at current and future strategies undertaken that invoke either target-based screening or phenotypic-based approaches, including the use of DNA-encoded libraries (DELs), display technologies and cyclic peptides, smaller molecular glue degraders, and covalent warhead ligands. These approaches are ripe for expanding the chemical space of PROTACs and usher in the advent of other emerging bifunctional modalities of proximity-based pharmacology.

show abstract

Section: Introductionmentioning

confidence: 95%

“… 47 ( C ) Structures of homo-PROTACs and related PROTACs composed with CRBN and VHL ligands: CM11, 48 Compound 15a, 49 CRBN-6-5-5-VHL, 50 Compound 14a, 51 and TD-165. 52 …”

Section: Introductionmentioning

confidence: 99%

E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones

2021

View full text Add to dashboard Cite

show abstract

“…Comparison of the physical properties of CLIPTAC precursor molecules(71)(72)(73) to published BET degraders(1)(2)(3) …”

mentioning

confidence: 99%

Current strategies for the design of PROTAC linkers: a critical review

Troup

Fallan

Baud

2020

Exploration of Targeted Anti-Tumor Therapy

216

182

View full text Add to dashboard Cite

PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules consisting of two ligands; an “anchor” to bind to an E3 ubiquitin ligase and a “warhead” to bind to a protein of interest, connected by a chemical linker. Targeted protein degradation by PROTACs has emerged as a new modality for the knock down of a range of proteins, with the first agents now reaching clinical evaluation. It has become increasingly clear that the length and composition of the linker play critical roles on the physicochemical properties and bioactivity of PROTACs. While linker design has historically received limited attention, the PROTAC field is evolving rapidly and currently undergoing an important shift from synthetically tractable alkyl and polyethylene glycol to more sophisticated functional linkers. This promises to unlock a wealth of novel PROTAC agents with enhanced bioactivity for therapeutic intervention. Here, the authors provide a timely overview of the diverse linker classes in the published literature, along with their underlying design principles and overall influence on the properties and bioactivity of the associated PROTACs. Finally, the authors provide a critical analysis of current strategies for PROTAC assembly. The authors highlight important limitations associated with the traditional “trial and error” approach around linker design and selection, and suggest potential future avenues to further inform rational linker design and accelerate the identification of optimised PROTACs. In particular, the authors believe that advances in computational and structural methods will play an essential role to gain a better understanding of the structure and dynamics of PROTAC ternary complexes, and will be essential to address the current gaps in knowledge associated with PROTAC design.

show abstract

“…Therefore, they have designed PROTACs to target CRBN or VHL itself. However, in all cases, the results have shown that the level of CRBN is decreased while the level of VHL is unchanged or increased, indicating that RPOTAC can ubiquitously degrade CRBN itself (Kim et al, 2019).…”

Section: Von Hippel-lindau-based Proteolysis Targeting Chimericsmentioning

confidence: 85%

“…Kim's team has also recruited CRBN and VHL by using pomalidomide and VH032, respectively (Kim et al, 2019). They are dedicated to knowing whether the E3 ligase itself can be ubiquitinated and degraded by another E3 ligase when two different E3 ligases are put together.…”

Section: Von Hippel-lindau-based Proteolysis Targeting Chimericsmentioning

confidence: 99%

PROTAC: An Effective Targeted Protein Degradation Strategy for Cancer Therapy

et al. 2021

View full text Add to dashboard Cite

Proteolysis targeting chimeric (PROTAC) technology is an effective endogenous protein degradation tool developed in recent years that can ubiquitinate the target proteins through the ubiquitin-proteasome system (UPS) to achieve an effect on tumor growth. A number of literature studies on PROTAC technology have proved an insight into the feasibility of PROTAC technology to degrade target proteins. Additionally, the first oral PROTACs (ARV-110 and ARV-471) have shown encouraging results in clinical trials for prostate and breast cancer treatment, which inspires a greater enthusiasm for PROTAC research. Here we focus on the structures and mechanisms of PROTACs and describe several classes of effective PROTAC degraders based on E3 ligases.

show abstract

Disordered region of cereblon is required for efficient degradation by proteolysis-targeting chimera

Cited by 29 publications

References 50 publications

E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones

E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones

Current strategies for the design of PROTAC linkers: a critical review

PROTAC: An Effective Targeted Protein Degradation Strategy for Cancer Therapy

Contact Info

Product

Resources

About