E3 Ligases: RING- or HECT-mediated ubiquitination?

A large number of cellular processes are regulated by the reversible conjugation of Ubiquitin (UB) proteins to substrates. UB-related research tools (including E1-, E2 and E3 Ligases) are now commercially available for further studying the role of this “Ubiquitin/Proteasome” pathway. Nevertheless, the identification of UB Ligase inhibitors remains challenging (1). Such bioactive small molecules are indeed important to further characterize the actors of this pathway, and to find new compounds for therapeutic applications.

Untill now, only a few bioactive molecules were characterized as Ub – Proteasome inhibitors. For example, TAME is known as a Ub-ligase inhibitor while Thialidomide and SMER3 specifically inhibit E3 UB ligase. (2-4)

Heclin: Inhibitor of HECT-Domain containing E3 Ubiquitin Ligases (tebu-bio | Focus Biomolecules) (10-1534)

Heclin: Inhibitor of HECT-Domain containing E3 Ubiquitin Ligases. Source: tebu-bio | Focus Biomolecules.

Recently, Mund et al. have identify a unique inhibitors that enable the distinction between E3 ligases with RING- and HECT-domains. (1) This new HECT Ligase inhibitor (Heclin) is the only bioactive compound commercially available known to specifically inhibit HECT-Ligases in vitro (and not RING-Ligases).

Interestingly, Heclin (2E-N-(4-Acetylphenyl)-3-(5-Ethylfuran-2-yl)Prop-2-Enamide) is now available as a ready-to-use compound (98% by TLC and soluble in DMSO (up to 40 mg/ml) or in ethanol (up to 10 mg/ml).

This inhibitor of HECT-Domain containing E3 Ubiquitin Ligases is thus a valuable research reagent for Drug discovery purposes and for distinguishing between RING- and HECT-mediated ubiquitination in R&D studies.

Sources:

1) Mund et al. (2014), Peptide and small molecule inhibitors of HECT-type ubiquitin ligases; Proc. Natl. Acad. Sci. USA, 111 16736

2) Weglicki et al. (1993), Inhibition of tumor necrosis factor-alpha by thalidomide in magnesium deficiency; Mol. Cell. Biochem., 129 195

3) Aghajanyy et al. (2010), Chemical genetics of TOR identifies an SCF family E3 ubiquitin ligase inhibitor; Nat. Biotechnol., 28 738

4) Zeng et al. (2010) Pharmacologic inhibition of the anaphase-promoting complex induces a spindle checkpoint-dependent mitotic arrest in the absence of spindle damage; Cancer Cell, 18 382

 

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