Department of Internal Medicine II, Division of Haematology, University Hospital Würzburg, Würzburg, Bavaria, Germany.
Br J Haematol. 2009 Nov;147(3):319-27. doi: 10.1111/j.1365-2141.2009.07852.x. Epub 2009 Aug 13.
The 90 kD heat shock protein (Hsp90) molecular chaperone sustains multiple components of oncogenic pathways and has recently emerged as a therapeutic target that is now being clinically tested in a number of malignancies. In order to address formulation issues and to deal with possible resistance mechanisms against small molecule Hsp90 inhibitors, a range of compounds based on different molecular scaffolds are now being developed. The present study preclinically tested the effects of the novel 2-aminothienopyrimidine class Hsp90 inhibitor NVP-BEP800, which is suitable for oral formulations, on multiple myeloma cells from established cell lines and on a larger cohort (n = 40) of primary myeloma samples. The drug effectively and specifically killed the majority of primary myeloma cells in coculture with bone marrow stromal cells and reliably entailed molecular consequences of Hsp90 blockade - such as survival pathway breakdown and client protein depletion - in multiple myeloma cells from cell lines as well as from patients. Collectively, the properties of this novel drug support clinical testing in multiple myeloma.
90kD 热休克蛋白（Hsp90）分子伴侣维持着多个致癌途径的组成部分，最近已成为一种治疗靶点，目前正在多种恶性肿瘤中进行临床测试。为了解决制剂问题，并应对针对小分子 Hsp90 抑制剂的可能耐药机制，目前正在开发基于不同分子支架的一系列化合物。本研究在临床前测试了新型 2-氨基噻吩并嘧啶类 Hsp90 抑制剂 NVP-BEP800 的效果，该抑制剂适合口服制剂，用于来自已建立的细胞系的多发性骨髓瘤细胞以及更大的队列（n=40）的原发性骨髓瘤样本。该药物在与骨髓基质细胞共培养时有效地、特异性地杀死了大多数原发性骨髓瘤细胞，并可靠地导致 Hsp90 阻断的分子后果 - 例如存活途径中断和客户蛋白耗竭 - 在来自细胞系和患者的多发性骨髓瘤细胞中。总的来说，这种新型药物的特性支持在多发性骨髓瘤中的临床测试。
