Molecular mechanisms of acquired proteasome inhibitor resistance.

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Kale AJ, Moore BS

Molecular mechanisms of acquired proteasome inhibitor resistance.

J Med Chem. 2012 Dec 13;55(23):10317-27. doi: 10.1021/jm300434z. Epub 2012 Oct 3.

PubMed ID

22978849 [ View in PubMed

]

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 beta-subunits. Additionally, we explore potential strategies to overcome PI resistance.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Bortezomib	Proteasome subunit beta type-1	IC 50 (nM)	53	N/A	N/A	Details
Bortezomib	Proteasome subunit beta type-5	IC 50 (nM)	7.9	N/A	N/A	Details