SCF E3 ubiquitin ligases as anticancer targets

Abstract

The SCF multisubunit complex (Skp1, Cullins, F-box proteins) E3 ubiquitin ligase, also known as CRL (Cullin-RING ubiquitin Ligase) is the largest E3 ubiquitin ligase family that promotes the ubiquitination of various regulatory proteins for targeted degradation, thus regulating many biological processes, including cell cycle progression, signal transduction, and DNA replication. The efforts to discover small molecule inhibitors of a SCF-type ligase or its components were expedited by the FDA approval of Bortezomib (also known as Velcade or PS-341), the first (and only) class of general proteasome inhibitor, for the treatment of relapsed/refractory multiple myeloma and mantle cell lymphoma. Although Bortezomib has demonstrated a certain degree of cancer cell selectivity with measurable therapeutic index, the drug is, in general, cytotoxic due to its inhibition of overall protein degradation. An alternative and ideal approach is to target a specific E3 ligase, known to be activated in human cancer, for a high level of specificity and selectivity with less associated toxicity, since such inhibitors would selectively stabilize a specific set of cellular proteins regulated by this E3. Here, we review recent advances in validation of SCF E3 ubiquitin ligase complex as an attractive anti-cancer target and discuss how MLN4924, a small molecule inhibitor of NEDD8-activating enzyme, can be developed as a novel class of anticancer agents by inhibiting SCF E3 ligase complex via removal of cullin neddylation. Finally, we discuss under future perspective how basic research on SCF biology will direct the drug discovery efforts surrounding this target.

Fig. 1. Ubiquitination cascade in protein degradation and functional regulation

Ubiquitin is first activated by ubiquitin activating enzyme, E1 and transferred to ubiquitin conjugating enzyme E2, and finally transferred to substrates by ubiquitin ligase E3, which recognizes the substrate and catalyzes the ubiquitin transfer. A single run of this ubiquitination reaction results in monoubiquitination of substrate protein with potential functional changes. Multiple runs of such a reaction lead to polyubiquitinatin of a substrate, which is either recognized by 26S proteasome for targeted degradation, if ubiquitin tag is in a K48 linkage, or subjected to activation, if it is in a K63 linkage.

Fig. 2. Targeting the SCF E3 ubiquitin ligase to trigger multiple cell killing pathways

SCF E3 ubiquitin ligase can be inactivated by targeting its oncogenic components, including RBX1/RBX2, Cul-4A, or Skp2 via siRNA silencing approach or by pharmaceutical inhibition of cullin neddylation with a NAE inhibitor, MLN4924. Inactivation of SCF E3 ligase causes the accumulation of its substrates which suppress cancer cell growth by triggering multiple cancer cell killing pathways, including apoptosis, senescence and autophagy with the mechanisms subjected to future investigation.