Cereblon versus VHL: Hijacking E3 ligases against each other using PROTACs

Girardini, Miriam; Maniaci, Chiara; Hughes, Scott J.; Testa, Andrea; Ciulli, A.

doi:10.1016/j.bmc.2019.02.048

Cited by 100 publications

(75 citation statements)

References 62 publications

(147 reference statements)

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“…Despite the extraordinary importance of VHL in the PROTAC eld, this E3 ligase has not yet been utilized for the successful development of CDK4/6 PROTACs and was even considered to be inappropriate. 37 We followed a combinatorial approach towards VHL-based PROTACs by assembling four different linkers of various lengths and lipophilicities and two VHL ligands bearing different exit vectors for linker connection, 43,61,62 which were ultimately incorporated into the nal palbociclib-derived CDK4/6d. Noteworthy, all PROTACs of the rst, 'amide' subseries (Tables 2 and S6, ESI †) had pronounced ability to suppress CDK4/6 protein levels.…”

Section: Vhl-based Protacsmentioning

confidence: 99%

Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders

Steinebach

Sosič

et al. 2020

Chem. Sci.

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Section: Vhl-based Protacsmentioning

confidence: 99%

Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders

Steinebach

Sosič

et al. 2020

Chem. Sci.

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“…Another approach developed recently is known as hetero-PROTACs, in which two ligand handles of two PROTACs [VHL and cereblon (CRBN)] were linked together via a linker molecule and tested for the potency of the compound to induce degradation of both ligases. The results showed that VHL could induce degradation of CRBN, but the reverse of this was not observed [ 225 ]. Considering the role of different E3 ligases in inducing the degradation of one another, hetero-PROTACs, can be tried against E3 ligases that are implemented in regulating TGFβ signaling.…”

Section: Emerging Roles Of Protacs and Molecular Gluesmentioning

confidence: 99%

E3 Ubiquitin Ligases: Key Regulators of TGFβ Signaling in Cancer Progression

Sinha

Iyengar

Dijke

2021

IJMS

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Transforming growth factor β (TGFβ) is a secreted growth and differentiation factor that influences vital cellular processes like proliferation, adhesion, motility, and apoptosis. Regulation of the TGFβ signaling pathway is of key importance to maintain tissue homeostasis. Perturbation of this signaling pathway has been implicated in a plethora of diseases, including cancer. The effect of TGFβ is dependent on cellular context, and TGFβ can perform both anti- and pro-oncogenic roles. TGFβ acts by binding to specific cell surface TGFβ type I and type II transmembrane receptors that are endowed with serine/threonine kinase activity. Upon ligand-induced receptor phosphorylation, SMAD proteins and other intracellular effectors become activated and mediate biological responses. The levels, localization, and function of TGFβ signaling mediators, regulators, and effectors are highly dynamic and regulated by a myriad of post-translational modifications. One such crucial modification is ubiquitination. The ubiquitin modification is also a mechanism by which crosstalk with other signaling pathways is achieved. Crucial effector components of the ubiquitination cascade include the very diverse family of E3 ubiquitin ligases. This review summarizes the diverse roles of E3 ligases that act on TGFβ receptor and intracellular signaling components. E3 ligases regulate TGFβ signaling both positively and negatively by regulating degradation of receptors and various signaling intermediates. We also highlight the function of E3 ligases in connection with TGFβ’s dual role during tumorigenesis. We conclude with a perspective on the emerging possibility of defining E3 ligases as drug targets and how they may be used to selectively target TGFβ-induced pro-oncogenic responses.

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“…Functionalization off of the terminal amine of VH032 has been extensively used in the design of bivalent degraders so we chose this position for linker appendage (Frost et al, 2016;Chan et al, 2018;Girardini et al, 2019). To connect the two ligands, different length alkyl (UNC6851-UNC6853) and PEG linkers (UNC6845-UNC6847) were incorporated to assess the distance required to induce successful EED degradation upon formation of the EED-degrader-VHL ternary complex (Table 1) (Cyrus et al, 2011).…”

Section: Design and Synthesis Of Eed-targeted Bivalent Degradersmentioning

confidence: 99%

Degradation of Polycomb Repressive Complex 2 with an EED-targeted Bivalent Chemical Degrader

Potjewyd

Turner

Beri

et al. 2019

Preprint

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Protein degradation via the use of bivalent chemical degraders provides an alternative strategy to block protein function and assess the biological roles of putative drug targets. This approach capitalizes on the advantages of small molecule inhibitors while moving beyond the restrictions of traditional pharmacology. Herein we report a first-in-class chemical degrader (UNC6852) that targets Polycomb Repressive Complex 2 (PRC2). UNC6852 contains an EED226 derived ligand and a ligand for VHL which bind to the WD40 aromatic cage of EED and CRL2 VHL , respectively, to induce proteasomal degradation of PRC2 components, EED, EZH2, and SUZ12. Degradation of PRC2 with UNC6852 blocks the histone methyltransferase activity of EZH2, decreasing H3K27me3 levels in HeLa cells and diffuse large B-cell lymphoma (DLBCL) cells containing an EZH2 Y641N gain-of-function mutation. UNC6852 degrades both wild type EZH2 and EZH2 Y641N , and additionally displays anti-proliferative effects in this cancer model system.

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Cereblon versus VHL: Hijacking E3 ligases against each other using PROTACs

Abstract: Graphical abstract

Cited by 100 publications

References 62 publications

Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders

Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders

E3 Ubiquitin Ligases: Key Regulators of TGFβ Signaling in Cancer Progression

Degradation of Polycomb Repressive Complex 2 with an EED-targeted Bivalent Chemical Degrader

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