Thanks to its capability to recruit the natural protein degradation system of a cell, PROTACs (PROteolysis TArgeting Chimera) appears as a very promising technology in cancer therapy and disease treatment. As a distributor of innovative reagents for life science researchers, tebu-bio provides you with all the necessary tools to develop or test your own PROTACs system.

In 2014, the U.S. Food and Drug Administration (FDA) approved the proteasome inhibiting drug Velcade (Bortezomib) for the retreatment of adult patients with Multiple Myeloma. My colleague Philippe Fixe discussed the use of Bortezomib in his post Proteasome inhibitor approved by FDA for Myeloma retreatment. In this post, I’d like to give you an overview of the compounds which can be used to inhibit proteasome activity and furthermore the activity of De-ubiquitinases (DUB, Isopeptidases), enzymes which catalyze the de-ubiquitination of ubiquitinated proteins and which are seen as very promising drug targets especially in cancer drug development.

With more than 100 types of cancers affecting any part of the body, cancer is one of the leading causes of death in the world. It has an enormous impact on well-being, both for those with the diagnosis and for those who surround them. Understanding and eventually treating or preventing this diverse group of cell growth diseases has been, and will continue to be a major focus of the medical and research communities.

A variety of popular cancer research tools exists and can be divised into categories. We’ll try to summarize them into few posts. Today, I’d like to focus on inhibitors known to be active on the Ubiquitin/Proteasome Pathway.

The U.S. Food and Drug Administration (FDA) has approved Velcade (Bortezomib) for the retreatment of adult patients with Multiple Myeloma who had previously responded to Velcade therapy and relapsed at least six months following completion of prior treatment. (1)

Bortezomib (marketed as Velcade by Millennium Pharmaceuticals Inc.) is a potent and selective Proteasome inhibitor. This di-peptide (formerly called PS-341)  was the first therapeutic proteasome to be tested in humans and approved in the U.S. for treating Multiple Myeloma (2, 3). Besides Multiple Myeloma, Bortezomib was also cleared to treat patients with Mantle Cell Lymphoma.

The proteasome regulates protein expression and function by degradation of ubiquitylated proteins. By interacting with the catalytic site of the 26S proteasome, Bortezomib prevents pro-apoptotic factor degradation thus allowing the activation of apoptosis in malignant cells.

This shows that the importance of the Proteasome / Ubiquitin pathway and small bioactive molecules in Drug Discovery research programs and anti-cancer therapy arsenal.

References

1. FDA Approves VELCADE® (bortezomib) Retreatment in Patients with Multiple Myeloma (August 2014), – Millennium (A Takeda Oncology Company).
2. Kane R.C. et al. “Velcade®: U.S. FDA Approval for the Treatment of Multiple Myeloma Progressing on Prior Therapy” The Oncologist (2003), vol. 8 – no. 6, p508-513. doi: 10.1634/theoncologist.8-6-508.
3. Velcade (bortezomib) is Approved for Initial Treatment of Patients with Multiple Myeloma (2008) – U.S. Food and Drug Administration (FDA)
   

   Bortezomib structure (Velcade®). Source: Focus Biomolecules.

See also

A selection of ultra-pure, cell permeable and potent Proteasome Inhibitors for R&D purposes:

• Aclacinomycin A
• Bortezomib 
• Carfilzomib (CFZ – marketed under the trade name Kyprolis, Onyx Pharmaceuticals, Inc.)
• Celastrol
• Epoxomicin (BU4061T)
• Lactacystin
• MG-132
• NSC-687852/b-AP15

What about you?

Which Proteasome inhibitor are you looking for? Leave a comment on this post or share your thoughts with other readers!