Research Papers:

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, Yang Yu, Man Wang, Zubin Zhang, Guodong Chen, Jie Li, Xiumin Zhou, Chunhua Qiao, Tingjun Hou _ and Xinliang Mao

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Oncotarget. 2014; 5:3836-3848. https://doi.org/10.18632/oncotarget.1657

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Juan Tang1,2,*, Jingyu Zhu1,2,*, Yang Yu3, Zubin Zhang1,2, Guodong Chen1,2, Xiumin Zhou4, Chunhua Qiao3, Tingjun Hou1,5, Xinliang Mao1,2,6

1 Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China

2 Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, The First Affiliated Hospital, Soochow University, Suzhou, China

3 Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Suzhou, China

4 Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China

5 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China

6 Collaborative Innovation Center of Hematology, Suzhou, China

* These authors contributed equally to this work.

Correspondence to:

Xinliang Mao, e-mail: [email protected]

Tingjun Hou, e-mail: [email protected]

Key words: C96; apoptosis; PI3K/AKT signal pathway; multiple myeloma; virtual screen

Received: December 05, 2013     Accepted: May 18, 2014     Published: May 21, 2014

Abbreviations: 4E-BP1, eIF4E-binding protein 1; DMSO, dimethyl sulfoxide; FITC, fluorescein isothiocyanate; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; IGF-1, insulin-like growth factor-1; IGF-1R, insulin-like growth factor-1 receptor; IMDM, Iscove's modified Dulbecco's medium; MM, multiple myeloma; mTOR, mammalian target of Rapamycin; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetra-sodium bromide; PARP, poly(ADP-ribose) polymerase; PDB, protein data bank; PI, propidium iodide; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog; SDS, sodium dodecyl sulfate; TBS, Tris-buffered saline.


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.

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