From Conception to Development: Investigating PROTACs Features for Improved Cell Permeability and Successful Protein Degradation

Cecchini, Carlotta; Pannilunghi, Sara; Tardy, Sébastien; Scapozza, Léonardo

doi:10.3389/fchem.2021.672267

Cited by 106 publications

(93 citation statements)

References 171 publications

(254 reference statements)

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“…Accordingly, genetic studies aimed at identifying SL interactors of SKP1 are highly warranted as the SL interactors are candidate drug targets that when inhibited are predicted to induce the selective killing of cancer cells harboring SKP1 defects. Beyond the genetic sensitization approaches detailed above, another promising strategy involves proteolysis-targeting chimeric molecules, or Protacs (reviewed in ( Sakamoto et al, 2001 ; Burslem and Crews, 2020 ; Cecchini et al, 2021 ; Hughes et al, 2021 )). The fundamental concept behind Protacs is that fusion proteins are created to link a specified target substrate to an F-box protein for SCF-mediated ubiquitination and degradation ( Sakamoto et al, 2001 ).…”

Section: Skp1 and The Scf Complex As Potential Therapeutic Targets In...mentioning

confidence: 99%

Aberrant SKP1 Expression: Diverse Mechanisms Impacting Genome and Chromosome Stability

Thompson

Rutherford

Lepage

et al. 2022

Front. Cell Dev. Biol.

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The S-phase Kinase-Associated Protein 1 (SKP1) is a core component of the SKP1, Cullin 1, F-box protein (SCF) complex, an E3 ubiquitin ligase that serves to poly-ubiquitinate a vast array of protein targets as a signal for their proteasomal degradation, thereby playing a critical role in the regulation of downstream biological processes. Many of the proteins regulated by SKP1 and the SCF complex normally function within pathways that are essential for maintaining genome stability, including DNA damage repair, apoptotic signaling, and centrosome dynamics. Accordingly, aberrant SKP1 and SCF complex expression and function is expected to disrupt these essential pathways, which may have pathological implications in diseases like cancer. In this review, we summarize the central role SKP1 plays in regulating essential cellular processes; we describe functional models in which SKP1 expression is altered and the corresponding impacts on genome stability; and we discuss the prevalence of SKP1 somatic copy number alterations, mutations, and altered protein expression across different cancer types, to identify a potential link between SKP1 and SCF complex dysfunction to chromosome/genome instability and cancer pathogenesis. Ultimately, understanding the role of SKP1 in driving chromosome instability will expand upon our rudimentary understanding of the key events required for genome/chromosome stability that may aid in our understanding of cancer pathogenesis, which will be critical for future studies to establish whether SKP1 may be useful as prognostic indicator or as a therapeutic target.

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Section: Skp1 and The Scf Complex As Potential Therapeutic Targets In...mentioning

confidence: 99%

Aberrant SKP1 Expression: Diverse Mechanisms Impacting Genome and Chromosome Stability

Thompson

Rutherford

Lepage

et al. 2022

Front. Cell Dev. Biol.

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“…Finally, PROTACs are large molecules without ideal molecular flexibility and water solubility which could hamper its oral absorption and cell permeability (Klein et al, 2020;Scott et al, 2020;Cecchini et al, 2021). Although most PROTACs in clinical trials are administered orally, their pharmacokinetic profile and metabolism could be further improved.…”

Section: Advantages and Disadvantages Of Protacs Technologymentioning

confidence: 99%

Options to Improve the Action of PROTACs in Cancer: Development of Controlled Delivery Nanoparticles

Juan¹,

Noblejas-López

Arenas-Moreira³

et al. 2022

Front. Cell Dev. Biol.

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Classical targeting in cancer focuses on the development of chemical structures able to bind to protein pockets with enzymatic activity. Some of these molecules are designed to bind the ATP side of the kinase domain avoiding protein activation and the subsequent oncogenic activity. A further improvement of these agents relies on the generation of non-allosteric inhibitors that once bound are able to limit the kinase function by producing a conformational change at the protein and, therefore, augmenting the antitumoural potency. Unfortunately, not all oncogenic proteins have enzymatic activity and cannot be chemically targeted with these types of molecular entities. Very recently, exploiting the protein degradation pathway through the ubiquitination and subsequent proteasomal degradation of key target proteins has gained momentum. With this approach, non-enzymatic proteins such as Transcription Factors can be degraded. In this regard, we provide an overview of current applications of the PROteolysis TArgeting Chimeras (PROTACs) compounds for the treatment of solid tumours and ways to overcome their limitations for clinical development. Among the different constraints for their development, improvements in bioavailability and safety, due to an optimized delivery, seem to be relevant. In this context, it is anticipated that those targeting pan-essential genes will have a narrow therapeutic index. In this article, we review the advantages and disadvantages of the potential use of drug delivery systems to improve the activity and safety of PROTACs.

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“…A final emerging therapeutic approach that may prove effective in cancers with SKP1, CUL1, or RBX1 alterations is PROTACS (reviewed in [107][108][109][110]). Briefly, PROTACS are chimeric proteins that link a protein target to an F-box protein for SCF-mediated proteolytic degradation [109].…”

Section: Targeting the Scf Complex For Cancer Treatmentsmentioning

confidence: 99%

The SCF Complex Is Essential to Maintain Genome and Chromosome Stability

Thompson

Rutherford

Lepage

et al. 2021

IJMS

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The SKP1, CUL1, F-box protein (SCF) complex encompasses a group of 69 SCF E3 ubiquitin ligase complexes that primarily modify protein substrates with poly-ubiquitin chains to target them for proteasomal degradation. These SCF complexes are distinguishable by variable F-box proteins, which determine substrate specificity. Although the function(s) of each individual SCF complex remain largely unknown, those that have been characterized regulate a wide array of cellular processes, including gene transcription and the cell cycle. In this regard, the SCF complex regulates transcription factors that modulate cell signaling and ensures timely degradation of primary cell cycle regulators for accurate replication and segregation of genetic material. SCF complex members are aberrantly expressed in a myriad of cancer types, with altered expression or function of the invariable core SCF components expected to have a greater impact on cancer pathogenesis than that of the F-box proteins. Accordingly, this review describes the normal roles that various SCF complexes have in maintaining genome stability before discussing the impact that aberrant SCF complex expression and/or function have on cancer pathogenesis. Further characterization of the SCF complex functions is essential to identify and develop therapeutic approaches to exploit aberrant SCF complex expression and function.

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From Conception to Development: Investigating PROTACs Features for Improved Cell Permeability and Successful Protein Degradation

Cited by 106 publications

References 171 publications

Aberrant SKP1 Expression: Diverse Mechanisms Impacting Genome and Chromosome Stability

Aberrant SKP1 Expression: Diverse Mechanisms Impacting Genome and Chromosome Stability

Options to Improve the Action of PROTACs in Cancer: Development of Controlled Delivery Nanoparticles

The SCF Complex Is Essential to Maintain Genome and Chromosome Stability

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