PMID- 26329846
OWN - NLM
STAT- MEDLINE
DCOM- 20160912
LR  - 20220321
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 5
DP  - 2015 Sep 2
TI  - SC06, a novel small molecule compound, displays preclinical activity against 
      multiple myeloma by disrupting the mTOR signaling pathway.
PG  - 12809
LID - 10.1038/srep12809 [doi]
LID - 12809
AB  - The mammalian target of rapamycin (mTOR) is extensively involved in multiple 
      myeloma (MM) pathophysiology. In the present study, we reported a novel small 
      molecule SC06 that induced MM cell apoptosis and delayed MM xenograft growth in 
      vivo. Oral administration of SC06 to mice bearing human MM xenografts resulted in 
      significant inhibition of tumor growth at doses that were well tolerated. 
      Mechanistic studies revealed that SC06 selectively inhibited the mTOR signaling 
      pathway but had no effects on other associated kinases, such as AKT, ERK, p38, 
      c-Src and JNK. Further studies showed that SC06-decreased mTOR activation was 
      associated with the downregulation of Raptor, a key component of the mTORC1 
      complex. SC06 also suppressed the phosphorylation of 4E-BP1 and P70S6K, two 
      typical substrates in the mTORC1 signaling pathway. Notably, expression of 
      Raptor, phosphorylation of mTOR and phosphorylated 4E-BP1 was also decreased in 
      the tumor tissues from SC06-treated mice, which was consistent with the cellular 
      studies. Therefore, given the potency and low toxicity, SC06 could be developed 
      as a potential anti-MM drug candidate by disrupting the mTOR signaling.
FAU - Han, Kunkun
AU  - Han K
AD  - Jiangsu Key Laboratory of Translational Research and Therapy for 
      Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical 
      Sciences, Soochow University, Suzhou, China.
FAU - Xu, Xin
AU  - Xu X
AD  - Jiangsu Key Laboratory of Translational Research and Therapy for 
      Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical 
      Sciences, Soochow University, Suzhou, China.
FAU - Xu, Zhuan
AU  - Xu Z
AD  - Department of Neurology, The First Affiliated Hospital of Soochow University, 
      Suzhou, China.
FAU - Chen, Guodong
AU  - Chen G
AD  - Jiangsu Key Laboratory of Translational Research and Therapy for 
      Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical 
      Sciences, Soochow University, Suzhou, China.
FAU - Zeng, Yuanying
AU  - Zeng Y
AD  - Jiangsu Key Laboratory of Translational Research and Therapy for 
      Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical 
      Sciences, Soochow University, Suzhou, China.
FAU - Zhang, Zubin
AU  - Zhang Z
AD  - Jiangsu Key Laboratory of Translational Research and Therapy for 
      Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical 
      Sciences, Soochow University, Suzhou, China.
FAU - Cao, Biyin
AU  - Cao B
AD  - Jiangsu Key Laboratory of Translational Research and Therapy for 
      Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical 
      Sciences, Soochow University, Suzhou, China.
FAU - Kong, Yan
AU  - Kong Y
AD  - Department of Neurology, The First Affiliated Hospital of Soochow University, 
      Suzhou, China.
FAU - Tang, Xiaowen
AU  - Tang X
AD  - Department of Hematology, the First Affiliated Hospital of Soochow University, 
      Suzhou, China.
FAU - Mao, Xinliang
AU  - Mao X
AD  - Jiangsu Key Laboratory of Translational Research and Therapy for 
      Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical 
      Sciences, Soochow University, Suzhou, China.
AD  - Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric 
      Diseases, Soochow University, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150902
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 
      (3-chloro-2-(2-((1-(4-(trifluoromethoxy)phenyl)-1H-pyrrol-2-yl)methylene)hydrazinyc)-5-(trifluoromethyl)pyridine)
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Aminopyridines)
RN  - 0 (Hydrazones)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (RPTOR protein, human)
RN  - 0 (Regulatory-Associated Protein of mTOR)
RN  - 0 (Small Molecule Libraries)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/metabolism
MH  - Aminopyridines/pharmacology/*therapeutic use
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects
MH  - Down-Regulation/drug effects
MH  - Female
MH  - HEK293 Cells
MH  - Humans
MH  - Hydrazones/pharmacology/*therapeutic use
MH  - Lysosomes/drug effects/metabolism
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice, Nude
MH  - Multiple Myeloma/*drug therapy/*metabolism/pathology
MH  - Multiprotein Complexes/metabolism
MH  - Proteasome Endopeptidase Complex/metabolism
MH  - Regulatory-Associated Protein of mTOR
MH  - Signal Transduction/*drug effects
MH  - Small Molecule Libraries/pharmacology/*therapeutic use
MH  - TOR Serine-Threonine Kinases/*metabolism
PMC - PMC4556980
EDAT- 2015/09/04 06:00
MHDA- 2016/09/13 06:00
PMCR- 2015/09/02
CRDT- 2015/09/03 06:00
PHST- 2015/03/27 00:00 [received]
PHST- 2015/07/08 00:00 [accepted]
PHST- 2015/09/03 06:00 [entrez]
PHST- 2015/09/04 06:00 [pubmed]
PHST- 2016/09/13 06:00 [medline]
PHST- 2015/09/02 00:00 [pmc-release]
AID - srep12809 [pii]
AID - 10.1038/srep12809 [doi]
PST - epublish
SO  - Sci Rep. 2015 Sep 2;5:12809. doi: 10.1038/srep12809.