A virtual screen identified C96 as a novel inhibitor of phosphatidylinositol 3-kinase that displays potent preclinical activity against multiple myeloma in vitro and in vivo
Juan Tang, Jingyu Zhu, Yu Yang, Zubing Zhang, Guodong Chen, Jie Li, Xiumin Zhou, Chunhua Qiao, Tingjun Hou*, Xinliang Mao*
Oncotarget. 2014 Jun 15;5(11):3836-48. (IF=6.627)
Abstract: The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is emerging as a promising therapeutic target for multiple myeloma (MM). In the present study, we performed a virtual screen against 800,000 of small molecule compounds by targeting PI3Kγ. C96, one of such compounds, inhibited PI3K activated by insulin-like growth factor-1 (IGF-1), but did not suppress IGF-1R activation. The cell-free assay revealed that C96 preferred to inhibit PI3Kα and δ, but was not active against AKT1, 2, 3 or mTOR. C96 inhibited PI3K activation in a time- and concentration-dependent manner. Consistent with its inhibition on PI3K/AKT, C96 downregulated the activation of mTOR, p70S6K, 4E-BP1, but did not suppress other kinases such as ERK and c-Src. Inhibition of the PI3K/AKT signaling pathway by C96 led to MM cell apoptosis which was demonstrated by Annexin V staining and activation of the pro-apoptotic signals. Furthermore, C96 displayed potent anti-myeloma activity in a MM xenograft model in nude mice. Oral administration of 100 mg/kg bodyweight almost fully suppressed tumor growth within 16 days, but without gross toxicity. Importantly, AKT activation was suppressed in tumor tissues from C96-treated mice, which was consistent with delayed tumor growth. Thus, we identified a novel PI3K inhibitor with a great potential for MM therapy.
