Development of Novel Peptide Aldehyde-Based Proteasome Inhibitors as Potential Anti-cancer Agents

Introduction

Proteasome serves as an important regulator of uncontrolled cellular proliferation or failed cell apoptosis. The two processes are depended on proteasome, and therefore cellular homeostasis could be potentially be restored to normal in cancer patients. The resistance to drugs and the lack of tumor specificity acts as a great hindrance to the treatment of neoplastic diseases (Adams, 2004). therefore, there is a need for creating a new potent class and specificity in anti-cancer drugs. According to Adams (2004), proteasome inhibitors induce apoptosis in a wide range of cancerous cells and which on the other hand impact on reduced toxicity in the normal cells. In this light, proteasome represents a novel therapeutic treatment target for cancer.

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The 20S proteasome and Cancer

The proteasome is essential for cellular functions due to its targeting for proteolysis. Eukaryotes deploy the ubiquitin-proteasome pathway as a central non-lysosomal pathway used for protein degradation. Lysosomal pathway degrades extracellular protein components imported into the cell by pinocytosis or endocytosis (Adams, 2004). On the contrary, proteasome controls the degradation of intracellular protein components. During proteolysis, proteins are targeted by the attachment of the polyubiquitin chain which disintegrates to small peptides and ubiquitin which is released is recycled in the process. The nucleus and eukaryotic cytoplasm contain 26S proteasome multi-subunit complex. However, the complex has 20S proteasome which is the catalytic core. The 20S proteasome has four heptameric rings which contain a and v subunits in its cylindrical structure. The outer rings are made of a units while the inner rings with proteolytically active sites are made of v subunits. The 20S proteasome is a threonine protease and therefore has an N-terminal of the v-subunit that provides the nucleophile that attacks the carbonyl groups of the target protein's peptide bond (Kisselev & Goldberg, 2001). Incorporating different catalytically active v subunits and association with the various regulatory complexes modulates the activity of the 20S catalytic core. For instance, three v-type units are synthesized on induced by interferon-gh. The three subunits, LMP2, LMP7, and MECL-1, replace the 20S proteasome's constitutive subunits forming the immunoproteasome. The modified catalytic core associates with accessory subunits resulting in a change in proteolytic activity. The changes favor the generation of peptide antigens. Regulation of proteasomal proteolysis can be attained by combining the ubiquitin-system; modulation of the 20S multi-catalytic protease by v-subunits remodeling as well as associating with regulatory complexes (Nandi et al., 2006). Since the ubiquitin-system allows for the degradation of a particular substrate and hence upregulating without affecting other substrates' proteolysis, proteasome function in regulating the metabolic pathways.

Novel proteasome inhibitors for anti-cancer drugs

Inhibition of proteasome provides a unique approach to cancer therapy which targets the protease function (Crawford et al., 2011). Peptide aldehydes were the first proteasome inhibitors applied. They work on cysteine and serine proteas. However, peptide aldehydes undergo rapid oxidation which yields inactive acids in cells and is released out of the cells by the MDR carrier system (Crawford et al., 2011). In that light, peptide aldehydes are not suitable candidates for use as cancer treatment therapeutic agents. Peptide boronates were developed from the adoption of boronic acid as a functional group to the peptide aldehydes. Inhibitors that contain boronic acid target proteasome selectively and bind non-covalently with the hydroxyl group of the N-terminal threonine proteasome residue (Thompson, 1977). They are not inactivated by oxidation and therefore are not transported out of the cell by MDR carriers. Peptide boronate bortezomib contains a boronic acid instead of carboxylic acid at the C-terminus. The boronic acid in bortezomib binds irreversibly to chymotrypsin-like v5 subunit of the 20S particle's catalytic chamber inhibiting the function of the proteasome (Chen et al. 2011). Bortezomib is the only approved proteasome inhibitor for clinical applications. However, it experiences some resistance in attaining full efficacy and efficiency. The targeted malignant cells may evolve a new resistance mechanism to bortezomib (Harer et al. 2012). Proteasome components can mutate or be overexpressed and therefore hamper bortezomib from inhibiting the function of the proteasome. Resistance to bortezomib can be in the form of failure of accumulation of pro-apoptotic proteins on treatment, overexpression of heat shock proteins and alteration of downstream effectors (Zaal et al., 2017).

Developed Inhibitors

The search for proteasome inhibitors has been in process for around 15 years. The inhibitors are a fundamental component of investigation on important ubiquitin-protease pathway's cellular processes (Manasanch & Orlowski, 2017). Proteasome pathway is targeting lead to new treatment for disorders such as cancer, inflammation, muscle dystrophies and immune diseases as in the case of bortezomib which is a potent inhibitor used in the treatment of multiple myeloma along with mantle cell lymphoma (Infante et al., 2016). New anti-cancer drugs have however been developed from the chemical structures identified in the early proteasome inhibitors. These drugs include CEP18770, Carfilzomib, and NPI-0052 and react with catalytic Thr1-O on the three v-active sites bonding covalently to the active sites.

Multiple myeloma is the second most common and known hematological malignancy. Multiple myeloma is a plasm cell disorder and contributes to 1.8% of new cancer diagnoses (Moreau t al., 2012). Combination of Carfilzomib-based regimens indicates high effectiveness in multiple myeloma and Waldenstrom's macroglogunemia therapies. MG132 is peptide aldehyde which effectively blocks the 26S proteasome complex' proteolytic activity (Han et al., 2009).

References

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Adams, J. (2004). The proteasome: a suitable antineoplastic target. Nature Reviews Cancer, 4(5), 349.

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Crawford, L. J., Walker, B., & Irvine, A. E. (2011). Proteasome inhibitors in cancer therapy. Journal of cell communication and signaling, 5(2), 101-110.

Han, Y. H., Moon, H. J., You, B. R., & Park, W. H. (2009). The effect of MG132, a proteasome inhibitor on HeLa cells in relation to cell growth, reactive oxygen species and GSH. Oncology reports, 22(1), 215-221.

Harer, S. L., Bhatia, M. S., & Bhatia, N. M. (2012). Proteasome inhibitors mechanism; Source for design of newer therapeutic agents. The Journal of antibiotics, 65(6), 279.

Infante, J. R., Mendelson, D. S., Burris, H. A., Bendell, J. C., Tolcher, A. W., Gordon, M. S., ... & Papadopoulos, K. P. (2016). A first-in-human dose-escalation study of the oral proteasome inhibitor oprozomib in patients with advanced solid tumors. Investigational new drugs, 34(2), 216-224.

Kisselev, A. F., & Goldberg, A. L. (2001). Proteasome inhibitors: from research tools to drug candidates. Chemistry & biology, 8(8), 739-758.

Manasanch, E. E., & Orlowski, R. Z. (2017). Proteasome inhibitors in cancer therapy. Nature reviews Clinical oncology, 14(7), 417.

Moreau, P., Richardson, P. G., Cavo, M., Orlowski, R. Z., San Miguel, J. F., Palumbo, A., & Harousseau, J. L. (2012). Proteasome inhibitors in multiple myeloma: 10 years later. Blood, 120(5), 947-959.

Nandi, D., Tahiliani, P., Kumar, A., & Chandu, D. (2006). The ubiquitin-proteasome system. Journal of biosciences, 31(1), 137-155.

Thompson, R. C. (1977). [19] Peptide aldehydes: Potent inhibitors of serine and cysteine proteases. In Methods in enzymology (Vol. 46, pp. 220-225). Academic Press.

Zaal, E. A., Wu, W., Jansen, G., Zweegman, S., Cloos, J., & Berkers, C. R. (2017). Bortezomib resistance in multiple myeloma is associated with increased serine synthesis. Cancer & metabolism, 5(1), 7.