2. Academic Validation
  3. The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitin-specific protease-14 and induces apoptosis of multiple myeloma cells

The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitin-specific protease-14 and induces apoptosis of multiple myeloma cells

  • Sci Rep. 2016 Jun 6;6:26979. doi: 10.1038/srep26979.
Xin Wang 1,  Magdalena Mazurkiewicz 2,  Ellin-Kristina Hillert 2,  Maria Hägg Olofsson 2,  Stefan Pierrou 3,  Per Hillertz 4,  Joachim Gullbo 5,  Karthik Selvaraju 1,  Aneel Paulus 6,  Sharoon Akhtar 7,  Felicitas Bossler 8,  Asher Chanan Khan 6 7,  Stig Linder 1 2,  Padraig D'Arcy 1
Affiliations

Affiliations

  • 1 Department of Medical Health Sciences (IMH), Linköping University, S-751 85 Linköping, Sweden.
  • 2 Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institute, S-171 76 Stockholm, Sweden.
  • 3 ESP Life Sciences Consulting AB, Box 119, 431 22 Mölndal, Sweden.
  • 4 Biosynchro in West AB, Karl Johansgatan 142, 414 51 Göteborg, Sweden.
  • 5 Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.
  • 6 Department of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA.
  • 7 Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
  • 8 German Cancer Research Center, DKFZ, Heidelberg, Germany.
PMID: 27264969 DOI: 10.1038/srep26979
Abstract

Inhibition of Deubiquitinase (DUB) activity is a promising strategy for Cancer therapy. VLX1570 is an inhibitor of Proteasome DUB activity currently in clinical trials for relapsed multiple myeloma. Here we show that VLX1570 binds to and inhibits the activity of ubiquitin-specific protease-14 (USP14) in vitro, with comparatively weaker inhibitory activity towards UCHL5 (ubiquitin-C-terminal hydrolase-5). Exposure of multiple myeloma cells to VLX1570 resulted in thermostabilization of USP14 at therapeutically relevant concentrations. Transient knockdown of USP14 or UCHL5 expression by electroporation of siRNA reduced the viability of multiple myeloma cells. Treatment of multiple myeloma cells with VLX1570 induced the accumulation of proteasome-bound high molecular weight polyubiquitin conjugates and an apoptotic response. Sensitivity to VLX1570 was moderately affected by altered drug uptake, but was unaffected by overexpression of BCL2-family proteins or inhibitors of Caspase activity. Finally, treatment with VLX1570 was found to lead to extended survival in xenograft models of multiple myeloma. Our findings demonstrate promising antiproliferative activity of VLX1570 in multiple myeloma, primarily associated with inhibition of USP14 activity.

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