SC06, a novel small molecule compound, displays preclinical activity against multiple myeloma by disrupting the mTOR signaling pathway.
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.
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
Kunkun
K
Han
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
Xin
X
Xu
Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Zhuan
Z
Xu
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
Guodong
G
Chen
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
Yuanying
Y
Zeng
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
Zubin
Z
Zhang
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
Biyin
B
Cao
Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Yan
Y
Kong
Department of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, China.
Xiaowen
X
Tang
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.|Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, China.
Xinliang
X
Mao
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000631:Aminopyridines / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology / Q000627:therapeutic use*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D046912:Multiprotein Complexes / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D000076223:Regulatory-Associated Protein of mTOR; D015398:Signal Transduction / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000494:pharmacology / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
C000610510:3-chloro-2-(2-((1-(4-(trifluoromethoxy)phenyl)-1H-pyrrol-2-yl)methylene)hydrazinyc)-5-(trifluoromethyl)pyridine; D048868:Adaptor Proteins, Signal Transducing; D000631:Aminopyridines; D006835:Hydrazones; D046912:Multiprotein Complexes; C463659:RPTOR protein, human; D000076223:Regulatory-Associated Protein of mTOR; D054852:Small Molecule Libraries; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex