Identification and characterisation of a novel heat shock protein 90 inhibitor ONO4140.
Identification and characterisation of a novel heat shock protein 90 inhibitor ONO4140.
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DOI：
10.1016/j.ejca.2014.04.017
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发表时间：
2014-07
期刊：
影响因子：
--
通讯作者：
Reddy EP
中科院分区：
文献类型：
--
作者：
Eachkoti R;Reddy MV;Lieu YK;Cosenza SC;Reddy EP
热休克蛋白 (Hsp) 90 是超级伴侣复合物的关键成分，可维持各种客户蛋白的功能活性构象。许多这些客户蛋白调节多种信号通路中的重要节点，促进癌细胞生长和存活。因此，Hsp90 抑制剂具有作为具有多效性的抗癌药物的潜力。鉴定具有更有利药理学特性的新型 Hsp90 抑制剂是癌症治疗的首要任务。为了实现这一目标，我们使用基于变性萤火虫荧光素酶重折叠的生化测定筛选了化合物库。该测定显示出高灵敏度、可靠性和重现性，Z 因子为 0.81 ± 0.17。本次筛选鉴定出的六种 Hsp90 抑制化合物的 IC50 值在 1.0 至 6 μM 之间，并通过使用多种肿瘤细胞系的 Cell Titer-Blue 细胞活力测定进一步表征其抗增殖活性。特别令人感兴趣的是 ONO4140 在三种不同的癌细胞系中具有最低的 GI50 值： DU-145、BT-474 和 K562 细胞系。这项研究还表明，肿瘤细胞短期暴露于 ONO4140 足以抑制 Hsp90 的催化活性，这是通过免疫沉淀破坏 Hsp90-p23 结合来评估的。这种短期暴露似乎会引发 Hsp90 客户蛋白（如 ErbB2/Her-2 和 Akt）的降解等事件，同时抑制生存信号，导致肿瘤细胞凋亡，如蛋白质印迹和 Caspase Glow-3,7 测定所示。该研究还表明，用 ONO4140 抑制 Hsp90 后，细胞凋亡通过 Caspase9-Caspase3 内在凋亡途径发生，这一过程可能是由 Akt 失活触发的。总之，我们发现了一类新型合成化合物，它们在临床前研究中显示出有效的 Hsp90 抑制作用。这类具有简单化学主链的新型合成 Hsp90 抑制剂的发现使我们能够进行进一步的结构修饰，以提高其在癌症治疗中的效力和药代动力学特性。
Heat shock protein (Hsp) 90 is a key component of the super-chaperone complex that maintains functionally active conformation of various client proteins. Many of these client proteins regulate important nodal points in multiple signalling pathways that promote cancer cell growth and survival. Inhibitors of Hsp90, therefore, have the potential of functioning as anti-cancer agents with pleiotropic effects. Identification of novel Hsp90 inhibitors with more favourable pharmacological properties is a priority in cancer therapy. To achieve this goal, we screened a compound library using a biochemical assay based on refolding of denatured firefly luciferase. The assay revealed high sensitivity, reliability and reproducibility with a Z-factor of 0.81 ± 0.17. Six Hsp90 inhibitory compounds identified by this screening with IC50 values between 1.0 and 6 μM were further characterised for anti-proliferative activity by Cell Titer-Blue Cell Viability Assay using multiple tumour cell lines. Of particular interest was ONO4140 with lowest GI50 values in three different cancer cell lines viz; DU-145, BT-474 and K562 cell lines. This study also revealed that short-term exposure of tumour cells with ONO4140 is sufficient to inhibit the catalytic activity of Hsp90, evaluated through disruption of Hsp90-p23 association by immunoprecipitation. This short term exposure appears to initiate events like degradation of Hsp90 client proteins such as ErbB2/Her-2 and Akt with concomitant inhibition of survival signalling leading to the apoptotic death of tumour cells as seen by western blotting and Caspase Glow-3,7 assay. The study also reveals that apoptosis following Hsp90 inhibition with ONO4140 occurs via Caspase9–Caspase3 intrinsic apoptotic pathway, a process that is likely triggered by inactivation of Akt. In conclusion, we have identified a novel class of synthetic compounds which show potent Hsp90 inhibitory action in preclinical studies. The discovery of this novel class of synthetic Hsp90 inhibitors with simple chemical backbone allows us to conduct further structural modifications to improve their potency and pharmacokinetic properties for use in cancer therapy.
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影响因子：
11.4
作者：
Blagosklonny, MV;Fojo, T;Neckers, LM
通讯作者：
Neckers, LM
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DOI：
10.1186/bcr1996
发表时间：
2008
期刊：
Breast cancer research : BCR
影响因子：
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作者：
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作者：
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