Identification of a promising PI3K inhibitor for the treatment of multiple myeloma through the structural optimization.
Identification of a promising PI3K inhibitor for the treatment of multiple myeloma through the structural optimization.
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通过结构优化鉴定出一种有前景的 PI3K 抑制剂用于治疗多发性骨髓瘤
DOI：
10.1186/1756-8722-7-9
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发表时间：
2014-01-15
影响因子：
28.5
通讯作者：
Mao X
中科院分区：
文献类型：
--
作者：
Han K;Xu X;Chen G;Zeng Y;Zhu J;Du X;Zhang Z;Cao B;Liu Z;Mao X
背景我们之前报道了一种PI3K抑制剂S14161，该抑制剂对多发性骨髓瘤（MM）和白血病表现出良好的临床前活性，但手性结构和溶解性差阻碍了其进一步应用。方法根据构效关系设计了6种S14161类似物；分别通过流式细胞术和蛋白质印迹分析化合物在细胞死亡和抑制 PI3K 方面的活性；在两个独立的异种移植模型上进行体内抗骨髓瘤活性。结果在六种类似物中，BENC-511 是最有效的化合物之一，可显着抑制 PI3K 活性并诱导 MM 细胞凋亡。 1 μM 的 BENC-511 能够灭活 PI3K 及其下游信号 AKT、mTOR、p70S6K 和 4E-BP1，但对其总蛋白表达没有影响。与其对 PI3K 活性的影响一致，BENC-511 诱导 MM 细胞凋亡，这一点通过 Caspase-3 和 PARP 的裂解得到证实。值得注意的是，添加胰岛素样生长因子1和白细胞介素6（MM细胞中PI3K激活的两个重要触发因素）部分阻断了BENC-511诱导的MM细胞死亡，这进一步证明PI3K信号通路对于BENC-511的抗骨髓瘤活性至关重要。此外，BENC-511 还表现出针对体内骨髓瘤的有效口服活性。在两个独立的多发性骨髓瘤异种移植模型中，口服 BENC-511 剂量为 50 毫克/千克体重，3 周内肿瘤生长降低达 80%，但毒性极小。 BENC-511 对 MM 肿瘤生长的抑制与 PI3K/AKT 活性降低和细胞凋亡增加有关。 结论 由于其有效的抗 MM 活性、低毒性 (LD50oral >1.5 g/kg) 和易于合成，BENC-511 可以通过抑制 PI3K/AKT 信号通路开发为治疗 MM 的有前途的药物。
BackgroundWe previously reported a PI3K inhibitor S14161 which displays a promising preclinical activity against multiple myeloma (MM) and leukemia, but the chiral structure and poor solubility prevent its further application.MethodsSix S14161 analogs were designed based on the structure–activity relationship; activity of the compounds in terms of cell death and inhibition of PI3K were analyzed by flow cytometry and Western blotting, respectively; anti-myeloma activityin vivowas performed on two independent xenograft models.ResultsAmong the six analogs, BENC-511 was one of the most potent compounds which significantly inhibited PI3K activity and induced MM cell apoptosis. BENC-511 was able to inactivate PI3K and its downstream signals AKT, mTOR, p70S6K, and 4E-BP1 at 1 μM but had no effects on their total protein expression. Consistent with its effects on PI3K activity, BENC-511 induced MM cell apoptosis which was evidenced by the cleavage of Caspase-3 and PARP. Notably, addition of insulin-like growth factor 1 and interleukin-6, two important triggers for PI3K activation in MM cells, partly blocked BENC-511-induced MM cell death, which further demonstrated that PI3K signaling pathway was critical for the anti-myeloma activity of BENC-511. Moreover, BENC-511 also showed potent oral activity against myelomain vivo. Oral administration of BENC-511 decreased tumor growth up to 80% within 3 weeks in two independent MM xenograft models at a dose of 50 mg/kg body weight, but presented minimal toxicity. Suppression of BENC-511 on MM tumor growth was associated with decreased PI3K/AKT activity and increased cell apoptosis.ConclusionsBecause of its potent anti-MM activity, low toxicity (LD50oral >1.5 g/kg), and easy synthesis, BENC-511 could be developed as a promising agent for the treatment of MM via suppressing the PI3K/AKT signaling pathway.
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影响因子：
20.3
作者：
Mao, Xinliang;Cao, Biyin;Schimmer, Aaron D.
通讯作者：
Schimmer, Aaron D.
影响因子：
20.3
作者：
Hsu, JH;Shi, YJ;Lichtenstein, A
通讯作者：
Lichtenstein, A
影响因子：
--
作者：
Markman B;Dienstmann R;Tabernero J
通讯作者：
Tabernero J
影响因子：
20.3
作者：
Hideshima, T;Chauhan, D;Anderson, KC
通讯作者：
Anderson, KC
DOI：
10.1073/pnas.0906461107
发表时间：
2010-06-22
影响因子：
11.1
作者：
Foukas, Lazaros C.;Berenjeno, Inma M.;Vanhaesebroeck, Bart
通讯作者：
Vanhaesebroeck, Bart