Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • News
  • Published:

Drug makers target ubiquitin proteasome pathway anew

Nature Biotechnology volume 33, pages 1115–1117 (2015)Cite this article

Subjects

A Correction to this article was published on 05 February 2016

This article has been updated

“The surprise is that the effects are dramatic for multiple myeloma, but they haven't been approved for anything else apart from mantle cell lymphoma,” says Alfred Goldberg, professor of cell biology at Harvard Medical School, in Boston, who pioneered the study of the proteasome in the 1970s and who co-founded MyoGenics (later ProScript), the company that discovered Velcade (bortezomib). Drug makers have struggled to hit components of the ubiquitin-proteasome system located beyond the traditional targets within the proteasome. “The interest in going just upstream of the proteasome is all about selectivity and better toxicity,” says Gerald Gavory, head of biology at Craigavon, Northern Ireland–based Almac Discovery.

The proteasome is of interest to drug developers because its main function—to break down unneeded, misfolded or damaged proteins into smaller peptides—is critical for many cellular processes and its dysregulation is implicated in many diseases, including cancer, neurological disorders and inflammation. The proteasome machinery is exquisite in its complexity. In gross structural terms, the eukaryotic 26S proteasome (its main components are denoted by their sedimentation coefficients) comprises a 20S catalytic core, flanked by one or two regulatory 19S caps. The 20S core complex resembles a cylindrical 'barrel', consisting of four stacked rings, each comprising seven subunits, surrounding a central cavity (Cell 23, 418–424, 2015). The outer rings contain inactive α-subunits, which operate as a gate. Catalytic sites on the β-subunits positioned towards the interior of the rings are responsible for the breakdown process, which involves caspase-like (β1), trypsin-like (β2) and chymotrypsin-like (β5) activities.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Change history

  • 13 January 2016

    In the penultimate paragraph, pevonedistat (TAK-924) was mis-identified as TAK-243, and the synergies referred to were seen in preclinical experiments, not in phase 1. The first two sentences in that paragraph “Less selective, perhaps, is targeting the E1 ubiquitin-activating enzyme. But Takeda is exploring these targets in combination with other therapies, having seen what senior scientist Allison Berger describes as “striking synergy” between an E1 ubiquitin-activating enzyme inhibitor TAK-243, in phase 1, and azacytidine in patients with acute myelogenous leukemia” have been replaced with “Targeting pathways linked to ubiquitin-like proteins remains at an early stage, too. Takeda is exploring the potential of pevonedistat (TAK-924), a first-in-class inhibitor of Nedd8 activating enzyme, in several cancers. A combination trial with azacitidine is underway in acute myelogenous leukemia, following what senior scientist Allison Berger called “striking synergy” seen in preclinical experiments.” The errors have been corrected in the HTML and PDF versions of the article.

Author information

Authors and Affiliations

  1. Dublin,

    Cormac Sheridan

Authors
  1. Cormac Sheridan
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sheridan, C. Drug makers target ubiquitin proteasome pathway anew. Nat Biotechnol 33, 1115–1117 (2015). https://doi.org/10.1038/nbt1115-1115

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nbt1115-1115

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing