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

Scientific Reports
Kunkun HanXinliang Mao

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.

References

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Citations

Mar 24, 2016·Annals of the New York Academy of Sciences·Heather FairfieldMichaela R Reagan
Mar 17, 2017·Anti-cancer Drugs·Hongwu MaoXinliang Mao
Jan 30, 2019·The Cancer Journal·Shaji K Kumar
Mar 22, 2019·The Kaohsiung Journal of Medical Sciences·Ying-Ying XuMing Chen
Mar 22, 2019·The Kaohsiung Journal of Medical Sciences·Jin-Guo YuMin-Hua Shi
May 8, 2019·The Kaohsiung Journal of Medical Sciences·Zi-Ming HuangJia-Li Tao
Dec 7, 2018·Journal of Experimental & Clinical Cancer Research : CR·Ying LiuFang Tian

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Methods Mentioned

BETA
xenograft

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis