PMID- 32271165
OWN - NLM
STAT- MEDLINE
DCOM- 20210519
LR  - 20240328
IS  - 2379-3708 (Electronic)
IS  - 2379-3708 (Linking)
VI  - 5
IP  - 7
DP  - 2020 Apr 9
TI  - IMPDH inhibitors for antitumor therapy in tuberous sclerosis complex.
LID - 135071 [pii]
LID - 10.1172/jci.insight.135071 [doi]
LID - e135071
AB  - Recent studies in distinct preclinical tumor models have established the 
      nucleotide synthesis enzyme inosine-5'-monophosphate dehydrogenase (IMPDH) as a 
      viable target for antitumor therapy. IMPDH inhibitors have been used clinically 
      for decades as safe and effective immunosuppressants. However, the potential to 
      repurpose these pharmacological agents for antitumor therapy requires further 
      investigation, including direct comparisons of available compounds. Therefore, we 
      tested structurally distinct IMPDH inhibitors in multiple cell and mouse tumor 
      models of the genetic tumor syndrome tuberous sclerosis complex (TSC). 
      TSC-associated tumors are driven by uncontrolled activation of the 
      growth-promoting protein kinase complex mechanistic target of rapamycin (mTOR) 
      complex 1 (mTORC1), which is also aberrantly activated in the majority of 
      sporadic cancers. Despite eliciting similar immunosuppressive effects, the IMPDH 
      inhibitor mizoribine, used clinically throughout Asia, demonstrated far superior 
      antitumor activity compared with the FDA-approved IMPDH inhibitor mycophenolate 
      mofetil (or CellCept, a prodrug of mycophenolic acid). When compared directly to 
      the mTOR inhibitor rapamycin, mizoribine treatment provided a more durable 
      antitumor response associated with tumor cell death. These results provide 
      preclinical support for repurposing mizoribine, over other IMPDH inhibitors, as 
      an alternative to mTOR inhibitors for the treatment of TSC-associated tumors and 
      possibly other tumors featuring uncontrolled mTORC1 activity.
FAU - Valvezan, Alexander J
AU  - Valvezan AJ
AD  - Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, 
      Boston, Massachusetts, USA.
FAU - McNamara, Molly C
AU  - McNamara MC
AD  - Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, 
      Boston, Massachusetts, USA.
FAU - Miller, Spencer K
AU  - Miller SK
AD  - Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, 
      Boston, Massachusetts, USA.
FAU - Torrence, Margaret E
AU  - Torrence ME
AD  - Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, 
      Boston, Massachusetts, USA.
FAU - Asara, John M
AU  - Asara JM
AD  - Division of Signal Transduction, Beth Israel Deaconess Medical Center, and 
      Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
FAU - Henske, Elizabeth P
AU  - Henske EP
AD  - Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 
      Boston, Massachusetts, USA.
FAU - Manning, Brendan D
AU  - Manning BD
AD  - Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, 
      Boston, Massachusetts, USA.
LA  - eng
GR  - P01 CA120964/CA/NCI NIH HHS/United States
GR  - P30 CA006516/CA/NCI NIH HHS/United States
GR  - R35 CA197459/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200409
PL  - United States
TA  - JCI Insight
JT  - JCI insight
JID - 101676073
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Ribonucleosides)
RN  - 4JR41A10VP (mizoribine)
RN  - EC 1.1.1.205 (IMP Dehydrogenase)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - HU9DX48N0T (Mycophenolic Acid)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Enzyme Inhibitors/*pharmacology
MH  - IMP Dehydrogenase/*antagonists & inhibitors/genetics/metabolism
MH  - Mechanistic Target of Rapamycin Complex 1/antagonists & 
      inhibitors/genetics/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Mycophenolic Acid/*pharmacology
MH  - Neoplasm Proteins/*antagonists & inhibitors/genetics/metabolism
MH  - Ribonucleosides/*pharmacology
MH  - Tuberous Sclerosis/*drug therapy/genetics/metabolism/pathology
PMC - PMC7205253
OTO - NOTNLM
OT  - Cancer
OT  - Genetic diseases
OT  - Metabolism
OT  - Therapeutics
OT  - Tumor suppressors
COIS- Conflict of interest: BDM is a shareholder and scientific advisory board member 
      for Navitor Pharmaceuticals and LAM Therapeutics.
EDAT- 2020/04/10 06:00
MHDA- 2021/05/20 06:00
PMCR- 2020/04/09
CRDT- 2020/04/10 06:00
PHST- 2019/11/18 00:00 [received]
PHST- 2020/03/05 00:00 [accepted]
PHST- 2020/04/10 06:00 [entrez]
PHST- 2020/04/10 06:00 [pubmed]
PHST- 2021/05/20 06:00 [medline]
PHST- 2020/04/09 00:00 [pmc-release]
AID - 135071 [pii]
AID - 10.1172/jci.insight.135071 [doi]
PST - epublish
SO  - JCI Insight. 2020 Apr 9;5(7):e135071. doi: 10.1172/jci.insight.135071.