Zhu Jingyu, Wang Man, Yu Yang, Qi Huixin, Han Kunkun, Tang Juan, Zhang Zubin, Zeng Yuanying, Cao Biyin, Qiao Chunhua, Zhang Hongjian, Hou Tingjun, Mao Xinliang
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China. Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
Oncotarget. 2015 Jan 1;6(1):185-95. doi: 10.18632/oncotarget.2688.
Recent clinical trials have demonstrated targeting PI3K pathway is a promising strategy for the treatment of blood cancers. To identify novel PI3K inhibitors, we performed a high throughput virtual screen and identified several novel small molecule compounds, including PIK-C98 (C98). The cell-free enzymatic studies showed that C98 inhibited all class I PI3Ks at nano- or low micromolar concentrations but had no effects on AKT or mTOR activity. Molecular docking analysis revealed that C98 interfered with the ATP-binding pockets of PI3Ks by forming H-bonds and arene-H interactions with specific amino acid residues. The cellular assays demonstrated that C98 specifically inhibited PI3K/AKT/mTOR signaling pathway, but had no effects on other kinases and proteins including IGF-1R, ERK, p38, c-Src, PTEN, and STAT3. Inhibition of PI3K by C98 led to myeloma cell apoptosis. Furthermore, oral administration of C98 delayed tumor growth in two independent human myeloma xenograft models in nude mice but did not show overt toxicity. Pharmacokinetic analyses showed that C98 was well penetrated into myeloma tumors. Therefore, through a high throughput virtual screen we identified a novel PI3K inhibitor that is orally active against multiple myeloma with great potential for further development.
近期的临床试验表明，靶向PI3K通路是治疗血液癌症的一种有前景的策略。为了鉴定新型PI3K抑制剂，我们进行了高通量虚拟筛选，并鉴定出了几种新型小分子化合物，包括PIK-C98（C98）。无细胞酶学研究表明，C98在纳摩尔或低微摩尔浓度下可抑制所有I类PI3K，但对AKT或mTOR活性无影响。分子对接分析显示，C98通过与特定氨基酸残基形成氢键和芳环-氢相互作用，干扰了PI3K的ATP结合口袋。细胞实验表明，C98特异性抑制PI3K/AKT/mTOR信号通路，但对包括IGF-1R、ERK、p38、c-Src、PTEN和STAT3在内的其他激酶和蛋白质无影响。C98对PI3K的抑制导致骨髓瘤细胞凋亡。此外，在两种独立的人骨髓瘤裸鼠异种移植模型中，口服C98可延缓肿瘤生长，但未显示明显毒性。药代动力学分析表明，C98能很好地渗透到骨髓瘤肿瘤中。因此，通过高通量虚拟筛选，我们鉴定出了一种新型PI3K抑制剂，该抑制剂对多发性骨髓瘤具有口服活性，具有进一步开发的巨大潜力。
