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Proteasome Inhibitors Versus E3 Ligase Inhibitors for Cancer Therapy

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Resistance to Proteasome Inhibitors in Cancer

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT))

Abstract

Molecular oncology has the potential to revolutionize cancer treatment owing to its focus on discrete, cancer-selective targets, as evident in the recent success of kinase inhibitors and antibody-based therapies. Because of the heterogeneous nature of cancer, however, not every tumor type can be addressed with an appropriately selective therapy and some respond best to drug combinations that include classical “toxic” agents. The ubiquitin-proteasome pathway, recently harnessed for cancer treatment with the clinical use of “toxic” proteasome inhibitors bortezomib and carfilzomib, affords targets that intuitively are highly selective, exemplified by inhibitors of E3 ligases, the ubiquitin-conjugating enzymes, as well as those that are intuitively nonselective, exemplified by the proteasomal proteases. In the last two decades, anticancer drug development based on these two target classes has proceeded in parallel, with the early results suggesting that the nonselective proteasome is the better target. Lately, however, it has become clear that (1) the “nonselective” proteasome target may be addressed in selective ways and (2) a clearer understanding of the E3 ligase reaction can lead to the design or discovery of efficacious inhibitors. Evidence supporting these notions and implications for cancer treatment going forward will be discussed.

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Abbreviations

ADME:

Absorption distribution, metabolism, excretion

DUB:

Deubiquitylating enzyme

ERAD:

Endoplasmic reticulum-associated degradation

HDM2:

Human variant of MDM2 = murine double minute 2 homologue (an E3 ligase)

IAP:

Inhibitor of apoptosis

RING:

Really interesting new gene

USP:

Ubiquitin-specific protease

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Authors and Affiliations

  1. Progenra, Inc., 277 Great Valley Parkway, Malvern, PA, 19355, USA

    Michael R. Mattern, Michael J. Eddins, Saket Agarwal, David E. Sterner, Matthew P. Kodrasov, K. G. Suresh Kumar, Jian Wu & Benjamin Nicholson

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  1. Michael R. Mattern
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  2. Michael J. Eddins
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  3. Saket Agarwal
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  4. David E. Sterner
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  5. Matthew P. Kodrasov
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  6. K. G. Suresh Kumar
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  7. Jian Wu
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  8. Benjamin Nicholson
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Correspondence to Michael R. Mattern .

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  1. Wayne State University, Detroit, Michigan, USA

    Q. Ping Dou

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© 2014 Springer International Publishing Switzerland

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Mattern, M.R. et al. (2014). Proteasome Inhibitors Versus E3 Ligase Inhibitors for Cancer Therapy. In: Dou, Q. (eds) Resistance to Proteasome Inhibitors in Cancer. Resistance to Targeted Anti-Cancer Therapeutics. Springer, Cham. https://doi.org/10.1007/978-3-319-06752-0_12

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