PMID- 25814533
OWN - NLM
STAT- MEDLINE
DCOM- 20150812
LR  - 20220408
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Linking)
VI  - 125
IP  - 23
DP  - 2015 Jun 4
TI  - Targeting deubiquitinase activity with a novel small-molecule inhibitor as 
      therapy for B-cell malignancies.
PG  - 3588-97
LID - 10.1182/blood-2014-10-605584 [doi]
AB  - Usp9x was recently shown to be highly expressed in myeloma patients with short 
      progression-free survival and is proposed to enhance stability of the survival 
      protein Mcl-1. In this study, we found that the partially selective Usp9x 
      deubiquitinase inhibitor WP1130 induced apoptosis and reduced Mcl-1 protein 
      levels. However, short hairpin RNA-mediated knockdown (KD) of Usp9x in myeloma 
      cells resulted in transient induction of apoptosis, followed by a sustained 
      reduction in cell growth. A compensatory upregulation of Usp24, a deubiquitinase 
      closely related to Usp9x, in Usp9x KD cells was noted. Direct Usp24 KD resulted 
      in marked induction of myeloma cell death that was associated with a reduction of 
      Mcl-1. Usp24 was found to sustain myeloma cell survival and Mcl-1 regulation in 
      the absence of Usp9x. Both Usp9x and Usp24 were expressed and activated in 
      primary myeloma cells whereas Usp24 protein overexpression was noted in some 
      patients with drug-refractory myeloma and other B-cell malignancies. Furthermore, 
      we improved the drug-like properties of WP1130 and demonstrated that the novel 
      compound EOAI3402143 dose-dependently inhibited Usp9x and Usp24 activity, 
      increased tumor cell apoptosis, and fully blocked or regressed myeloma tumors in 
      mice. We conclude that small-molecule Usp9x/Usp24 inhibitors may have therapeutic 
      activity in myeloma.
CI  - (c) 2015 by The American Society of Hematology.
FAU - Peterson, Luke F
AU  - Peterson LF
AD  - Department of Internal Medicine/Division of Hematology/Oncology, University of 
      Michigan School of Medicine and Comprehensive Cancer Center, Ann Arbor, MI;
FAU - Sun, Hanshi
AU  - Sun H
AD  - Department of Internal Medicine/Division of Hematology/Oncology, University of 
      Michigan School of Medicine and Comprehensive Cancer Center, Ann Arbor, MI;
FAU - Liu, Yihong
AU  - Liu Y
AD  - Department of Internal Medicine/Division of Hematology/Oncology, University of 
      Michigan School of Medicine and Comprehensive Cancer Center, Ann Arbor, MI;
FAU - Potu, Harish
AU  - Potu H
AD  - Department of Internal Medicine/Division of Hematology/Oncology, University of 
      Michigan School of Medicine and Comprehensive Cancer Center, Ann Arbor, MI;
FAU - Kandarpa, Malathi
AU  - Kandarpa M
AD  - Department of Internal Medicine/Division of Hematology/Oncology, University of 
      Michigan School of Medicine and Comprehensive Cancer Center, Ann Arbor, MI;
FAU - Ermann, Monika
AU  - Ermann M
AD  - Department of Drug Discovery Alliance, Evotec, Abingdon, Oxfordshire, United 
      Kingdom;
FAU - Courtney, Stephen M
AU  - Courtney SM
AD  - Department of Drug Discovery Alliance, Evotec, Abingdon, Oxfordshire, United 
      Kingdom;
FAU - Young, Matthew
AU  - Young M
AD  - Department of Pharmacology, University of Michigan School of Medicine and 
      Comprehensive Cancer Center, Ann Arbor, MI;
FAU - Showalter, Hollis D
AU  - Showalter HD
AD  - Department of Medicinal Chemistry and.
FAU - Sun, Duxin
AU  - Sun D
AD  - Department of Pharmaceutical Sciences, University of Michigan College of 
      Pharmacy, Ann Arbor, MI; and.
FAU - Jakubowiak, Andrzej
AU  - Jakubowiak A
AD  - Section of Hematology/Oncology, University of Chicago Medical Center, Chicago, 
      IL.
FAU - Malek, Sami N
AU  - Malek SN
AD  - Department of Internal Medicine/Division of Hematology/Oncology, University of 
      Michigan School of Medicine and Comprehensive Cancer Center, Ann Arbor, MI;
FAU - Talpaz, Moshe
AU  - Talpaz M
AD  - Department of Internal Medicine/Division of Hematology/Oncology, University of 
      Michigan School of Medicine and Comprehensive Cancer Center, Ann Arbor, MI;
FAU - Donato, Nicholas J
AU  - Donato NJ
AD  - Department of Internal Medicine/Division of Hematology/Oncology, University of 
      Michigan School of Medicine and Comprehensive Cancer Center, Ann Arbor, MI;
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150326
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Cyanoacrylates)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (MCL1 protein, human)
RN  - 0 (Myeloid Cell Leukemia Sequence 1 Protein)
RN  - 0 (Pyridines)
RN  - 0 (USP24 protein, human)
RN  - 0 (USP9X protein, human)
RN  - 0 (degrasyn)
RN  - EC 3.4.19.12 (Ubiquitin Thiolesterase)
SB  - IM
CIN - Blood. 2015 Jun 4;125(23):3522-3. PMID: 26045592
MH  - Animals
MH  - Apoptosis/*drug effects/genetics
MH  - Cell Line, Tumor
MH  - Cyanoacrylates/*pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Inhibitors/*pharmacology
MH  - Female
MH  - Gene Expression Regulation, Enzymologic/drug effects
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - Lymphoma, Mantle-Cell/*drug therapy/enzymology/genetics/pathology
MH  - Male
MH  - Mice
MH  - Multiple Myeloma/*drug therapy/enzymology/genetics/pathology
MH  - Myeloid Cell Leukemia Sequence 1 Protein/genetics/metabolism
MH  - Pyridines/*pharmacology
MH  - Ubiquitin Thiolesterase/*antagonists & inhibitors/genetics/metabolism
EDAT- 2015/03/31 06:00
MHDA- 2015/08/13 06:00
CRDT- 2015/03/28 06:00
PHST- 2014/10/08 00:00 [received]
PHST- 2015/03/19 00:00 [accepted]
PHST- 2015/03/28 06:00 [entrez]
PHST- 2015/03/31 06:00 [pubmed]
PHST- 2015/08/13 06:00 [medline]
AID - S0006-4971(20)31579-2 [pii]
AID - 10.1182/blood-2014-10-605584 [doi]
PST - ppublish
SO  - Blood. 2015 Jun 4;125(23):3588-97. doi: 10.1182/blood-2014-10-605584. Epub 2015 
      Mar 26.