Discovery of XL888: A novel tropane-derived small molecule inhibitor of HSP90
Discovery of XL888: A novel tropane-derived small molecule inhibitor of HSP90
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DOI：
10.1016/j.bmcl.2012.07.052
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发表时间：
2012-09-01
影响因子：
2.7
通讯作者：
Rice, Kenneth D.
中科院分区：
文献类型：
--
作者：
Bussenius, Joerg;Blazey, Charles M.;Rice, Kenneth D.
在结构指导下，对托烷衍生的 HTS 命中进行了修改，以优化 HSP90 抑制和理想的体内特性。通过迭代 SAR 开发过程，12i (XL888) 被发现并在 PD 研究中显示可降低 HSP90 客户蛋白含量。此外，在 NCI-N87 小鼠异种移植模型中进行的功效实验证明，某些给药方案中的肿瘤消退。 (C) 2012 Elsevier Ltd. 保留所有权利。
With structural guidance, tropane-derived HTS hits were modified to optimize for HSP90 inhibition and a desirable in vivo profile. Through an iterative SAR development process 12i (XL888) was discovered and shown to reduce HSP90 client protein content in PD studies. Furthermore, efficacy experiments performed in a NCI-N87 mouse xenograft model demonstrated tumor regression in some dosing regimens. (C) 2012 Elsevier Ltd. All rights reserved.