Cereblon versus VHL: Hijacking E3 Ligases Against Each Other Using PROTACs

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

doi:10.26434/chemrxiv.7698185.v2

Cited by 15 publications

(18 citation statements)

References 43 publications

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“…VHL is known to be a crucial substrate recognition subunit of Cullin-RING E3 ubiquitin ligase complexes; it is employed to induce ubiquitination and subsequent proteasomal degradation of target proteins. 45 More importantly, VHL is able to regulate the stability of HIF1α. 23 HIFα is hydroxylated in an oxygen-containing environment and binds to VHL protein to trigger the ubiquitin-proteasome proteolytic pathway, following degradation by ubiquitination.…”

Section: Discussionmentioning

confidence: 99%

microRNA-222-Mediated VHL Downregulation Facilitates Retinoblastoma Chemoresistance by Increasing HIF1α Expression

Zhao

Sun

2020

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Retinoblastoma (RB) is the most common primary intraocular tumor in children. Chemoresistance is the major obstacle for treatment of these tumors. This study aims to determine whether or not downregulating microRNA-222 (miR-222) could serve as a potential therapeutic target for preventing chemoresistance in RB treatment. METHODS. Differentially expressed miR-222 in RB samples and its downstream target genes were predicted using bioinformatics methods. The expression of miR-222 was altered by mimic or inhibitor to examine its role in RB cell in response to the chemotherapeutic agent vincristine (VCR). Further bioinformatic analysis predicted involvement of the stability of hypoxia-inducible factor 1α (HIF1α) protein in regulation of the von Hippel-Lindau (VHL) tumor suppressor, followed by characterization of the effect of VHL on the ubiquitin-proteasome degradation of HIF1α. Next, VHL or HIF1α was overexpressed to determine their effects on RB cell activities after VCR treatment. In vivo assays were performed on nude mice to further verify the in vitro results. RESULTS. miR-222 is highly expressed in RB tissues and cells and was found to facilitate resistance of RB cells to VCR. Of note, miR-222 specifically bound to and negatively regulated VHL. VHL could inhibit the stability of HIF1α and promote the degradation of ubiquitin-proteasome, thus reducing HIF1α expression to attenuate VCR resistance in RB cells. Moreover, inhibition of miR-222 in combination with VCR suppressed tumor formation in nude mice. CONCLUSIONS. miR-222 promotes the expression of HIF1α by targeting VHL, thus accelerating the resistance of RB cells to the chemotherapeutic agent VCR.

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Section: Discussionmentioning

confidence: 99%

microRNA-222-Mediated VHL Downregulation Facilitates Retinoblastoma Chemoresistance by Increasing HIF1α Expression

Zhao

Sun

2020

Invest. Ophthalmol. Vis. Sci.

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“…Importantly, the exit vector chosen can have a large impact on ternary complex formation (Cromm and Crews, 2017;Chan et al, 2018;Smith et al, 2019). 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. 2020

Cell Chemical Biology

152

114

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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. Here, we report a chemical degrader (UNC6852) that targets polycomb repressive complex 2 (PRC2). UNC6852 contains an EED226derived 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 EZH2 gain-of-function mutations. UNC6852 degrades both wild-type and mutant EZH2, and additionally displays anti-proliferative effects in this cancer model system.

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“…In continuation of the homo-PROTAC approach, Ciulli et al [72] investigated the hypothesis that the E3 ligases themselves could be hijacked against each other using a heterodimerizing PROTAC, leading either to degradation of both E3 ligases or preferential degradation of one E3 ligase. A library of CRBN -VHL PROTACs was designed and synthesized, using pomalidomide as CRBN handle and as for the VHL handle, structural modifications were designed on two known VHL ligands, including different attachment points of the linker.…”

Section: Homo-protacsmentioning

confidence: 99%

PROTACs– a game-changing technology

Konstantinidou

Zhang

et al. 2019

Expert Opinion on Drug Discovery

127

109

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Introduction: Proteolysistargeting chimeras (PROTACs) have emerged as a new modality with the potential to revolutionize drug discovery. PROTACs are heterobifunctional molecules comprising of a ligand targeting a protein of interest, a ligand targeting an E3 ligase and a connecting linker. The aim is instead of inhibiting the target to induce its proteasomal degradation. Areas covered: PROTACs, due to their bifunctional design, possess properties that differentiate them from classical inhibitors. A structural analysis, based on published crystal aspects, kinetic features and aspects of selectivity are discussed. Specific types such as homoPROTACs, PROTACs targeting Tau protein and the first PROTACs recently entering clinical trials are examined. Expert opinion: PROTACs have shown remarkable biological responses in challenging targets, including an unprecedented selectivity over protein family members and even efficacy starting from weak or unspecific binders. Moreover, PROTACs are standing out from classical pharmacology by inducing the degradation of the target protein and not merely its inhibition. However, there are also challenges in the field, such as the rational structure optimization, the evolution of computational tools, limited structural data and the greatly anticipated clinical data. Despite the remaining hurdles, PROTACs are expected to soon become a new therapeutic category of drugs.

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Cereblon versus VHL: Hijacking E3 Ligases Against Each Other Using PROTACs

Cited by 15 publications

References 43 publications

microRNA-222-Mediated VHL Downregulation Facilitates Retinoblastoma Chemoresistance by Increasing HIF1α Expression

microRNA-222-Mediated VHL Downregulation Facilitates Retinoblastoma Chemoresistance by Increasing HIF1α Expression

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

PROTACs– a game-changing technology

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