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  • Review Article
  • Published:

SCF ubiquitin ligase-targeted therapies

Nature Reviews Drug Discovery volume 13, pages 889–903 (2014)Cite this article

Subjects

Key Points

  • The ubiquitin–proteasome system (UPS) has links to numerous diseases, and the clinical success of proteasome inhibitors suggests the potential to develop drugs targeting other components of the UPS. In certain cases, the specific inhibition of individual components of the UPS may provide better therapeutic outcomes than does broad inhibition of the proteasome.

  • F-box proteins are the targeting subunits of the SKP1-CUL1-F-box protein (SCF) ubiquitin ligase complexes, the best characterized of the mammalian cullin–RING ligase family of E3 ubiquitin ligases. In mammals, there are approximately 70 F-box proteins, each thought to be able to target multiple substrates, facilitating the regulation of diverse cellular pathways.

  • SCF complexes are dysregulated in several diseases by overexpression of the F-box protein, by mutation (genetic deletion or point mutations) of the F-box protein, or by disrupting the pathways that control F-box protein–substrate targeting.

  • In cases in which an SCF complex is overactive, the inhibition of SCF-mediated degradation can be achieved via competitive inhibition between substrate and F-box protein, allosteric inhibition that disrupts the interaction between substrate and F-box protein, or via the inhibition of SCF complex assembly.

  • In cases in which SCF activity is defective in disease, SCF activity can by reconstituted through bivalent small molecules that re-target the substrate and/or 'molecular glue'-like molecules that restore substrate–F-box protein binding.

  • Although an underdeveloped area, SCF complexes are promising drug targets, and as the substrates and functions of orphan F-box proteins are discovered, further drug targets will become apparent. Several compounds targeting E3 ligases have been developed, hinting that effective drugs targeting other SCF ubiquitin ligase activities may also be developed.

Abstract

The clinical successes of proteasome inhibitors for the treatment of cancer have highlighted the therapeutic potential of targeting this protein degradation system. However, proteasome inhibitors prevent the degradation of numerous proteins, which may cause adverse effects. Increased specificity could be achieved by inhibiting the components of the ubiquitin–proteasome system that target specific subsets of proteins for degradation. F-box proteins are the substrate-targeting subunits of SKP1–CUL1–F-box protein (SCF) ubiquitin ligase complexes. Through the degradation of a plethora of diverse substrates, SCF ubiquitin ligases control a multitude of processes at the cellular and organismal levels, and their dysregulation is implicated in many pathologies. SCF ubiquitin ligases are characterized by their high specificity for substrates, and these ligases therefore represent promising drug targets. However, the potential for therapeutic manipulation of SCF complexes remains an underdeveloped area. This Review explores and discusses potential strategies to target SCF-mediated biological processes to treat human diseases.

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Figure 1: Ubiquitin-mediated degradation.
Figure 2: The modular structure of SCF ubiquitin ligases and points of potential therapeutic intervention.
Figure 3: Strategies to manipulate SCF ubiquitin ligase activity.

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Acknowledgements

The authors thank T. Cardozo, C. Crewes, R. Deshaies, R. Kumar, R. Mallampalli, K. Nakayama, N. Wilkie and N. Zheng for critically reading the manuscript and apologise for the omission of many colleagues' work owing to space constraints. J.R.S. is a Special Fellow of The Leukemia & Lymphoma Society. J.K.P. is supported by a fellowship from the Lymphoma Research Foundation. Work in the Pagano laboratory is supported by grants (R37CA076584 and R01GM057587) from the US National Institutes of Health. M.P. is an Investigator of the Howard Hughes Medical Institute.

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Author notes

  1. Jeffrey R. Skaar and Julia K. Pagan: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, 10016, New York, USA

    Jeffrey R. Skaar, Julia K. Pagan & Michele Pagano

  2. Howard Hughes Medical Institute,

    Michele Pagano

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  1. Jeffrey R. Skaar
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Correspondence to Michele Pagano.

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FURTHER INFORMATION

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PowerPoint slides

Glossary

Ubiquitin

A 76-amino acid protein that can be covalently conjugated to other proteins through amine groups at the amino terminus or on internal lysine residues. Proteins can be monoubiquitylated or polyubiquitylated. Chains assembled via K48 (in most cases) and K11 linkages target substrate proteins to the proteasome for degradation.

Ubiquitylation

The process of covalently attaching ubiquitin to another protein. Ubiquitylation is accomplished via an enzymatic cascade of an E1 ubiquitin activating enzyme, an E2 ubiquitin conjugating enzyme, and an E3 ubiquitin ligase.

Proteasome

A large protein complex that catalyses the proteolytic destruction of proteins.

Ubiquitin–proteasome system

The ubiquitin–proteasome system (UPS) collectively refers to the proteins regulating ubiquitin-dependent protein degradation by the proteasome.

RING domains

Really interesting new gene (RING) domains coordinate zinc ions and often mediate binding of E2 ubiquitin conjugating enzymes.

HECT domain

Homologous to E6 carboxy-terminus (HECT) domains define a sub-family of E3 ubiquitin ligases. HECT domains recruit the E2 ubiquitin conjugating enzyme and participate directly in substrate ubiquitylation by forming a thioester bond with ubiquitin.

Cullin (CUL)–RING-ligases

(CRLs). A family of multisubunit E3 ubiquitin ligases that share a common architecture. The eight CRLs are each based on a different cullin scaffold protein, and each complex recruits a small RING protein and a unique set of substrate adaptor proteins.

SCF complexes

(SKP1–CUL1–F-box protein complexes; also known as CRL1). A family of multi-subunit E3 ubiquitin ligases. As listed in the name, SCF complexes contain a cullin 1 (CUL1) scaffold, and an S-phase kinase-associated protein 1 (SKP1) that bridges CUL1 to a variable F-box- containing protein, of which there are ~70 in mammals. These complexes also contain the small RING protein RBX1.

NEDD8

A small, ubiquitin-like protein that can be conjugated to other proteins to alter their function. The best-defined and most abundant substrates for neddylation are the cullin family of proteins, which require neddylation for their activity.

Degrons

A small region of a substrate protein that is recognized by the E3 ubiquitin ligase and is required for substrate binding and ubiquitylation. Minimal degrons are often short peptide sequences. A variety of mechanisms, including post-translational modification of residues within the degron, can regulate access and binding of the degron to the E3 ubiquitin ligase.

Pharmacophores

The features of a small-molecule ligand that dictate the interactions with macromolecular targets that are responsible for its biological activities.

Cryptochrome proteins

The two mammalian cryptochrome proteins (cryptochrome 1 (CRY1) and CRY2) function in the circadian clock machinery as transcriptional repressors.

Hepatitis C virus (HCV) NS5A

A multifunctional protein generated from the cleavage of a polyprotein precursor during HCV infection and required for productive HCV infection.

Proteolysis targeting chimeras

(PROTACs). Bi-functional compounds, molecules or proteins that bind an E3 ubiquitin ligase on one end and another protein that is not the normal E3 substrate on the other end. PROTACs retarget the E3 ligase activity to new substrates.

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Skaar, J., Pagan, J. & Pagano, M. SCF ubiquitin ligase-targeted therapies. Nat Rev Drug Discov 13, 889–903 (2014). https://doi.org/10.1038/nrd4432

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