Name: Protac-1
Brand: BOC Sciences
Rating: 5 (1 reviews)

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2 years

Mechanism

Target: Protac-1 targets methionine aminopeptidase-2 through an ovalicin-derived recognition element.

Binding site: Ovalicin covalently engages the catalytic active site of MetAP-2.

Mechanism of action: Protac-1 is the original proof-of-concept PROTAC molecule, designed to recruit methionine aminopeptidase-2 to the SCFβ-TRCP ubiquitin ligase complex. It contains an ovalicin-derived MetAP-2 ligand linked to an IκBα phosphopeptide recognized by β-TRCP. This bifunctional architecture artificially brings MetAP-2 into proximity with SCF machinery, enabling ubiquitination and proteasome-dependent degradation. Although peptide-based and primarily historical, Protac-1 remains important for illustrating the foundational event-driven principle of targeted protein degradation: chemically induced proximity can redirect cellular ubiquitination toward a selected protein.

Applications

• PROTAC-Mediated Targeted Degradation: Protac-1 is designed to facilitate the selective degradation of specific proteins within the cellular environment. This application allows researchers to study protein function by removing the protein of interest, providing insights into cellular pathways and potential therapeutic targets.

• Protein Homeostasis Studies: Utilizing Protac-1 in research enables the investigation of cellular protein homeostasis mechanisms. By degrading target proteins, scientists can explore how cells maintain equilibrium and respond to protein dysregulation, enhancing our understanding of disease pathology.

• Drug Discovery and Development: Protac-1 serves as a valuable tool in drug discovery, aiding in the identification of novel drug targets through targeted protein degradation. Researchers can assess the therapeutic potential of degrading specific proteins, accelerating the development of innovative treatments.

• Mechanistic Pathway Analysis: With Protac-1, scientists can dissect complex signaling pathways by selectively degrading components involved in these networks. This approach helps elucidate protein interactions and pathway dynamics, contributing to a more comprehensive understanding of cellular processes.

1. Protacs: Chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation.

Sakamoto, K.M., Kim, K.B., Kumagai, A., Mercurio, F., Crews, C.M. and Deshaies, R.J., 2001. Proceedings of the National Academy of Sciences, 98(15), pp.8554-8559.

The intracellular levels of many proteins are regulated by ubiquitin-dependent proteolysis. One of the best-characterized enzymes that catalyzes the attachment of ubiquitin to proteins is a ubiquitin ligase complex, Skp1-Cullin-F box complex containing Hrt1 (SCF). We sought to artificially target a protein to the SCF complex for ubiquitination and degradation. To this end, we tested methionine aminopeptidase-2 (MetAP-2), which covalently binds the angiogenesis inhibitor ovalicin. A chimeric compound, protein-targeting chimeric molecule 1 (Protac-1), was synthesized to recruit MetAP-2 to SCF. One domain of Protac-1 contains the IκBα phosphopeptide that is recognized by the F-box protein β-TRCP, whereas the other domain is composed of ovalicin. We show that MetAP-2 can be tethered to SCFβ-TRCP, ubiquitinated, and degraded in a Protac-1-dependent manner. In the future, this approach may be useful for conditional inactivation of proteins, and for targeting disease-causing proteins for destruction.

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It is commonly abbreviated as: C₁V₁ = C₂V₂