The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitin-specific protease-14 and induces apoptosis of multiple myeloma cells.
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.
Department of Medical Health Sciences (IMH), Linköping University, S-751 85 Linköping, Sweden.
Xin
X
Wang
Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institute, S-171 76 Stockholm, Sweden.
Magdalena
M
Mazurkiewicz
Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institute, S-171 76 Stockholm, Sweden.
Ellin-Kristina
EK
Hillert
Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institute, S-171 76 Stockholm, Sweden.
Maria Hägg
MH
Olofsson
ESP Life Sciences Consulting AB, Box 119, 431 22 Mölndal, Sweden.
Stefan
S
Pierrou
Biosynchro in West AB, Karl Johansgatan 142, 414 51 Göteborg, Sweden.
Per
P
Hillertz
Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.
Joachim
J
Gullbo
Department of Medical Health Sciences (IMH), Linköping University, S-751 85 Linköping, Sweden.
Karthik
K
Selvaraju
Department of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA.
Aneel
A
Paulus
Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
Sharoon
S
Akhtar
German Cancer Research Center, DKFZ, Heidelberg, Germany.
Felicitas
F
Bossler
Department of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA.|Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
Asher Chanan
AC
Khan
Department of Medical Health Sciences (IMH), Linköping University, S-751 85 Linköping, Sweden.|Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institute, S-171 76 Stockholm, Sweden.
Stig
S
Linder
Department of Medical Health Sciences (IMH), Linköping University, S-751 85 Linköping, Sweden.
Padraig
P
D'Arcy
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001381:Azepines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001597:Benzylidene Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D004795:Enzyme Stability; D005260:Female; D006801:Humans; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy*; D025821:Polyubiquitin / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D059748:Proteolysis; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001381:Azepines; D001597:Benzylidene Compounds; D061988:Proteasome Inhibitors; C509299:USP14 protein, human; C000623193:VLX1570; D025821:Polyubiquitin; C421245:UCHL5 protein, human; D043222:Ubiquitin Thiolesterase; D046988:Proteasome Endopeptidase Complex