SCo6, 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 SCo6 that induced MM cell apoptosis and delayed MM xenograft growth in vivo. Oral administration of SCo6 to mice bearing human MM xenografts resulted in significant inhibition of tumor growth at doses that were well tolerated. Mechanistic studies revealed that SCo6 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 SCo6-decreased mTOR activation was associated with the downregulation of Raptor, a key component of the mTORC1 complex. SCo6 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 SCo6-treated mice, which was consistent with the cellular studies. Therefore, given the potency and low toxicity, SCo6 could be developed as a potential anti-MM drug candidate by disrupting the mTOR signaling.