Development of proteasome inhibitors as research tools and cancer drugs - PubMed (original) (raw)

Development of proteasome inhibitors as research tools and cancer drugs

Alfred L Goldberg. J Cell Biol. 2012.

Abstract

The proteasome is the primary site for protein degradation in mammalian cells, and proteasome inhibitors have been invaluable tools in clarifying its cellular functions. The anticancer agent bortezomib inhibits the major peptidase sites in the proteasome's 20S core particle. It is a "blockbuster drug" that has led to dramatic improvements in the treatment of multiple myeloma, a cancer of plasma cells. The development of proteasome inhibitors illustrates the unpredictability, frustrations, and potential rewards of drug development but also emphasizes the dependence of medical advances on basic biological research.

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Figures

Figure 1.

Figure 1.

Structure and function of the 26S proteasome. (A) Structure and components of the 26S proteasome. For more accurate images, see Lander et al. (2012) and Lasker et al. (2012). (B) Location of active sites in the 20S proteasome core. There are three types of proteolytic sites in the 20S proteasome’s central chamber, and each β ring contains three active sites. Bortezomib and MG132 act primarily on the chymotrypsin-like site in the β subunit but also inhibit the caspase-like site at high concentrations.

Figure 2.

Figure 2.

Structure and mechanism of action of proteasome inhibitors. (A) Structure of MG132, an inhibitor widely used in uncovering many cellular functions of the proteasome. (B and C) Structure of bortezomib (B), the inhibitor used to treat multiple myeloma, and its chemical reaction with the active site terminal threonine residue of the β5 subunit (C). (D) The primary mechanisms by which bortezomib causes death of myeloma cells.

References

    1. Adams J., Palombella V.J., Sausville E.A., Johnson J., Destree A., Lazarus D.D., Maas J., Pien C.S., Prakash S., Elliott P.J. 1999. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res. 59:2615–2622 - PubMed
    1. Baumeister W., Walz J., Zühl F., Seemüller E. 1998. The proteasome: paradigm of a self-compartmentalizing protease. Cell. 92:367–380 10.1016/S0092-8674(00)80929-0 - DOI - PubMed
    1. Bodine S.C., Latres E., Baumhueter S., Lai V.K.-M., Nunez L., Clarke B.A., Poueymirou W.T., Panaro F.J., Na E., Dharmarajan K., et al. 2001. Identification of ubiquitin ligases required for skeletal muscle atrophy. Science. 294:1704–1708 10.1126/science.1065874 - DOI - PubMed
    1. Borissenko L., Groll M. 2007. 20S proteasome and its inhibitors: crystallographic knowledge for drug development. Chem. Rev. 107:687–717 10.1021/cr0502504 - DOI - PubMed
    1. Cenci S., Oliva L., Cerruti F., Milan E., Bianchi G., Raule M., Mezghrani A., Pasqualetto E., Sitia R., Cascio P. 2012. Pivotal Advance: Protein synthesis modulates responsiveness of differentiating and malignant plasma cells to proteasome inhibitors. J. Leukoc. Biol. 10.1189/jlb.1011497 - DOI - PubMed

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