SC06, a novel small molecule compound, displays preclinical activity against multiple myeloma by disrupting the mTOR signaling pathway

Kunkun Han; Xin Xu; Zhuan Xu; Guodong Chen; Yuanying Zeng; Zubin Zhang; Biyin Cao; Yan Kong; Xiaowen Tang; Xinliang Mao

doi:10.1038/srep12809

SC06, a novel small molecule compound, displays preclinical activity against multiple myeloma by disrupting the mTOR signaling pathway

Sci Rep. 2015 Sep 2:5:12809. doi: 10.1038/srep12809.

Authors

Kunkun Han¹, Xin Xu¹, Zhuan Xu², Guodong Chen¹, Yuanying Zeng¹, Zubin Zhang¹, Biyin Cao¹, Yan Kong², Xiaowen Tang³, Xinliang Mao^{1

4}

Affiliations

¹ Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
² Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, China.
³ Department of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, China.
⁴ Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, China.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism
Aminopyridines / pharmacology
Aminopyridines / therapeutic use*
Animals
Apoptosis / drug effects
Cell Line, Tumor
Cell Survival / drug effects
Down-Regulation / drug effects
Female
HEK293 Cells
Humans
Hydrazones / pharmacology
Hydrazones / therapeutic use*
Lysosomes / drug effects
Lysosomes / metabolism
Mechanistic Target of Rapamycin Complex 1
Mice, Nude
Multiple Myeloma / drug therapy*
Multiple Myeloma / metabolism*
Multiple Myeloma / pathology
Multiprotein Complexes / metabolism
Proteasome Endopeptidase Complex / metabolism
Regulatory-Associated Protein of mTOR
Signal Transduction / drug effects*
Small Molecule Libraries / pharmacology
Small Molecule Libraries / therapeutic use*
TOR Serine-Threonine Kinases / metabolism*

Substances

3-chloro-2-(2-((1-(4-(trifluoromethoxy)phenyl)-1H-pyrrol-2-yl)methylene)hydrazinyc)-5-(trifluoromethyl)pyridine
Adaptor Proteins, Signal Transducing
Aminopyridines
Hydrazones
Multiprotein Complexes
RPTOR protein, human
Regulatory-Associated Protein of mTOR
Small Molecule Libraries
Mechanistic Target of Rapamycin Complex 1
TOR Serine-Threonine Kinases
Proteasome Endopeptidase Complex