Molecular mechanisms of acquired proteasome inhibitor resistance - PubMed (original) (raw)

. 2012 Dec 13;55(23):10317-27.

doi: 10.1021/jm300434z. Epub 2012 Oct 3.

Affiliations

Molecular mechanisms of acquired proteasome inhibitor resistance

Andrew J Kale et al. J Med Chem. 2012.

Abstract

The development of proteasome inhibitors (PIs) has transformed the treatment of multiple myeloma and mantle cell lymphoma. To date, two PIs have been FDA approved, the boronate peptide bortezomib and, most recently, the epoxyketone peptide carfilzomib. However, intrinsic and acquired resistance to PIs, for which the underlying mechanisms are poorly understood, may limit their efficacy. In this Perspective, we discuss recent advances in the molecular understanding of PI resistance through acquired bortezomib resistance in human cell lines and evolved salinosporamide A (marizomib) resistance in bacteria. Resistance mechanisms discussed include the up-regulation of proteasome subunits and mutations of the catalytic β-subunits. Additionally, we explore potential strategies to overcome PI resistance.

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Figures

Figure 1

Figure 1

The Ubiquitin-proteasome system. Poly-ubiquitination of cellular proteins by the cascade of E1, E2 and E3 enzymes assigns substrate proteins for 26S proteasomal degradation. Poly-Ub proteins are recognized and unfolded by the 19S regulatory particle and fed into the proteolytic 20S core particle for destruction by the three catalytically active subunits, β5, β2, and β1.

Figure 2

Figure 2

Chemical structure of selected proteasome inhibitors.

Figure 3

Figure 3

Substrate binding analysis of 1 and the β5-subunit of the Saccharomyces cerevisiae 20S proteasome. a. Dashed lines represent H-bonding with the distance shown in Å. Mutations observed at Ala49, Ala50 and Thr21 may disrupt H-bonding and decrease PI binding. Adapted in part from Structure, Vol. 14, Groll, M., Berkers, C. R., Ploegh, H. L., and Ovaa, H., “Crystal structure of the boronic-acid based proteasome inhibitor bortezomib in complex with the yeast 20S proteasome,” 451–456, Copyright 2006, with permission from Elsevier. b. Crystal structure of the S1 binding pocket with 1 bound. Image created using PDB file 2F16, chain K rendered in PyMol.

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