Will the Ubiquitin System Furnish as Many Drug Targets as Protein Kinases?

Abstract

Protein phosphorylation and protein ubiquitination regulate most aspects of cell life, and defects in these control mechanisms cause cancer and many other diseases. In the past decade, protein kinases have become one of the most important classes of drug targets for the pharmaceutical industry. In contrast, drug discovery programs that target components of the ubiquitin system have lagged behind. In this Perspective, we discuss the reasons for the delay in this pipeline, the drugs targeting the ubiquitin system that have been developed, and new approaches that may popularize this area of drug discovery in the future.

miR-200 promotes the mesenchymal to epithelial transition by suppressing multiple members of the Zeb2 and Snail1 transcriptional repressor complexes

“…In fact, the maximally tolerated bortezomib dose in mice was needed to achieve proteasome inhibition of xenografted tumors. At least 14 novel proteasome inhibitors are in advanced clinical development and one, carfilzomib, has been approved for multiple myeloma (Cohen et al, 2010 BPLER were also attractive because they are highly enriched for T-IC, which normally represent a minor subpopulation of breast cancer cell lines and are difficult to study in vitro. In fact the only other human TNBC cell line enriched for T-IC is derived from HMLER by stable knockdown of E-cadherin (HMLER-shEcad) (Gupta et al, 2009).…”

Decreased expression of the SPOP gene is associated with poor prognosis in glioma

“…Many proteins implicated in the ubiquitin pathways are related to tumor progression. In recent years, there have been many approaches to target the ubiquitin system in cancer therapy (26,27). The E3 ubiquitin ligases are considered the most important components in these approaches because they bind directly to the target proteins (26).…”

Conformational dynamics control ubiquitin-deubiquitinase interactions and influence in vivo signaling

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