Current Topics in Medicinal Chemistry - Volume 11, Issue 23, 2011

In this issue of Current Topics in Medicinal Chemistry, we highlight several aspects of the medicinal chemistry of ubiquitin- proteasome pathway (UPP) and its relevance in drug discovery by collecting comprehensive reviews from several experts working in this field. More than 80% normal and abnormal intracellular proteins were degraded by UPP. A growing body of evidence suggested that derangements of UPP could lead to many disorders, such as malignancies, neurodegenerative diseases and possible systematic autoimmunity. Due to making fundamental breakthroughs in understanding the function of this essential pathway, three distinguished scientists won the 2004 Nobel Prize in Chemistry. This pathway was clinically validated as an effective target for cancer therapy since the first proteasome inhibitor bortezomib was approved for the treatment of multiple myeloma by FDA in 2003. Nowadays, several inhibitors are being investigated in Phase I and II for the treatment of several types of tumors. Furthermore, many compounds are being discovered and developed as candidates for the treatment of other diseases, such as diabetes, Parkinson's disease (PD) and Alzheimer disease (AD). I would like to express my sincere appreciation to all the authors for their outstanding contributions. I also thank Dr. Allen Reitz, Editor-in-Chief, for inviting me to prepare this special issue of Current Topics in Medicinal Chemistry and great thanks are also owned to Dr. Rhoda Weber Joseph for his help during my preparation of this issue. I hope that this issue will be an informative contribution to the field and will represent an important reference work for the medicinal chemists involved in ubiquitin-proteasome pathway.

The 26S proteasome is the enzymatic core engine of the ubiquitin and proteasome dependent proteolytic system (UPS), the major eukaryotic pathway for regulated protein degradation. The UPS plays a pivotal role in cellular protein turnover, protein quality control, antigen processing, signal transduction, cell cycle regulation, cell differentiation and apoptosis, inspiring in-depth studies of proteasome structure and function and the search for selective inhibitors. Structural studies revealed that the 26S proteasome comprises up to two 19S regulatory caps flanking a cylindrical 20S core particle, which houses the proteolytic subunits and is present in all kingdoms of life. This review highlights current understanding of 20S architecture, maturation and assembly, the mechanism for selective degradation of protein substrates targeted for destruction, and relationships to other proteases. This knowledge base has benefited from structurally diverse proteasome inhibitors discovered from unique sources, including terrestrial and marine actinomycetes that produce the β-lactone-γ- lactam superfamily of inhibitors, including omuralide, salinosporamide A (marizomib; NPI-0052) and the cinnabaramides. These “minimalist inhibitors” utilize dense functionality to maximum efficiency for potent and selective proteasome inhibition and have advanced from biochemical tools to potential agrochemicals and anticancer agents. In this review, lessons learned from the β-lactone-γ-lactam superfamily are presented, with an emphasis on their unique binding mechanisms elucidated through structural biology in concert with medicinal chemistry. Distinctions between slowly reversible and irreversible inhibitors are discussed, together with the relationship of irreversible binding at the molecular level to prolonged duration proteasome inhibition in tumor cells, and in vitro and in vivo efficacy.

The Rho family small GTPases of the Ras superfamily play key roles in regulating diverse signaling pathways that control a myriad of fundamental cellular processes such as cytoskeletal dynamics, cell cycle progression, gene expression, cell polarity, migration and cell transformation. The Rho GTPases cycle between an active GTP-bound and an inactive GDP-bound form, which is controlled by many regulators including GEFs, GAPs and GDIs. Recent studies have revealed a new layer of regulation for Rho GTPases, indicating that several members of the Rho family of small GTPases including RhoA, Rac1, and RhoBTB, as well as the Ras family member Rap1B, are also regulated by the ubiquitinproteasome pathway, which plays important roles in controlling cell polarity, migration, cell transformation and actin dynamics. Importantly, regulators for Rho GTP-GDP cycling such as RhoGDI and Rho-GEF ECT2 were also found to be modulated by the ubiquitin pathway. In this review, we focus on how ubiquitin signaling guides the fate and function of Rho GTPases and their regulators, especially how the E3 ubiquitin ligase Smurf1 regulates cell polarity and motility through targeting RhoA for ubiquitination and degradation.

Selective degradation of proteins by the ubiquitin-proteasome pathway is a critical determinant for maintaining cellular homeostasis. Most intracellular proteins are degraded by the proteasome, a multicatalytic enzyme complex containing a 20S catalytic core and two 19S regulatory complexes. Many proteasome target proteins are involved in the regulation of important processes of carcinogenesis and cancer cell survival, such as cell cycle progression, cell proliferation, differentiation and apoptosis. Indeed, the ubiquitin-proteasome-dependent degradation pathway plays an essential role in both the up-regulation of cell proliferation and down-regulation of cell death in human cancer cells. Both in vitro and in vivo experimental and clinical results have demonstrated the potential use of proteasome inhibitors as novel anticancer drugs. Proteasome inhibition in cancer cells leads to accumulation of pro-apoptotic target proteins followed by induction of cell death. The clinical efficacy of the proteasome inhibitor bortezomib toward multiple myeloma and other hematologic malignancies provides the “proof of concept” that targeting the proteasome is a promising strategy for cancer treatment. Several other proteasome inhibitors have also been identified from natural resources, such as marine microbial metabolites, green tea polyphenols, flavonoids, and medicinal compounds. Additionally, the use of metal complexes as proteasome inhibitors has also been investigated as a potential anticancer strategy. The clinical significance of targeting the tumor survival-associated proteasome pathway for cancer treatment, intervention and prevention will be discussed.

Salinosporamide A (4), a secondary metabolite of the marine actinomycete Salinispora tropica, is a potent inhibitor of 20S proteasome that is currently in clinical trials for the treatment of cancers. Herein, we described various synthetic strategies of 4 and summarized the SAR of 4 and its analogs.

The proteasome, a large multisubunit protease complex, has been extensively investigated over the years, greatly enhancing our understanding of critical roles that the proteasome plays in cells. The FDA approval of bortezomib for the treatment of multiple myeloma and mantle cell lymphoma has validated the proteasome as an anticancer target. However, the undesirable toxicities of these agents limit their broad utility. The immunoproteasome, an alternative form of the constitutive proteasome, has recently been explored as a therapeutic target. While the immunoproteasome, normally expressed in cells of hematopoietic origin, has been shown to be associated with various types of cancer and inflammatory diseases, its multifaceted function is not fully understood due to the lack of appropriate molecular probes. In this review, recent advances in the immunoproteasome field are covered, including potential implications in disease states. In particular, recent developments in immunoproteasome-specific inhibitors are emphasized.

The target proteasome has been the focus of drug discovery since the first drug bortezomib was launched in 2003. Many structurally diverse proteasome inhibitors were discovered and even some of them entered the clinical trials. Due to rapid technological progress in chemistry, bioinformatics, structural biology and computer technology, computeraided drug design (CADD) plays a more and more important role in today's drug discovery. Many CADD technologies were employed in designing various inhibitors of proteasome in the past years. This review gives a global description of the development of computer-aided proteasome inhibitor design by using different commercial or academic software. The binding modes of some structurally novel inhibitors with proteasome were visualized with these new technologies.