Discovery of a novel small inhibitor RJ19 targeting to human Hsp90
Discovery of a novel small inhibitor RJ19 targeting to human Hsp90
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发现针对人 Hsp90 的新型小抑制剂 RJ19
DOI：
10.1007/s41365-017-0300-1
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发表时间：
2017-10-01
影响因子：
2.8
通讯作者：
He, Jian-Hua
中科院分区：
文献类型：
--
作者：
Cao, Hui-Ling;Lyu, Kai-Kai;He, Jian-Hua
热休克蛋白90 （Hsp90）可以通过帮助多种客户蛋白的折叠、构象成熟和激活来促进癌细胞的生长和增殖。因此，Hsp90作为一种抗癌药物靶点受到越来越多的关注。报道的Hsp90抑制剂有几个局限性，如溶解度差、生物利用度有限和肝毒性。本研究采用基于片段的药物发现方法设计并合成了一种新型的小分子抑制剂RJ19。通过x射线衍射（分辨率极限，2.0埃，PDB代码4L90）测定了Hsp90(N) -RJ19的晶体结构。详细分析了Hsp90(N)-RJ19的晶体结构，并分别与天然Hsp90(N)、Hsp90(N)-ATP和Hsp90(N) -GDM进行了比较。结果表明，RJ19与Hsp90(N)在atp结合口袋处相互作用，表明RJ19可能取代核苷酸与Hsp90(N)结合，导致Hsp90的伴侣功能失效。因此，RJ19已成为一种很有前景的抗癌先导化合物。Hsp90(N)=-RJ19中L2 Loop的重排和位移在功能失效中起着关键作用，这也使得口袋变宽变长，便于后期RJ19的结构修饰。RJ19与Hsp90(N)之间复杂的晶体结构及其相互作用为新型抗癌药物的设计和优化提供了合理的依据。
Heat shock protein 90 (Hsp90) can promote growth and proliferation of cancer cells by helping in folding, conformational maturation, and activation of various client proteins. Therefore, Hsp90 has been paid more attention to as an anticancer drug target. Reported Hsp90 inhibitors have several limitations such as poor solubility, limited bioavailability, and hepatotoxicity. Here, a novel small inhibitor RJ19 has been designed using fragment-based drug discovery and synthesized. Additionally, a crystal structure of Hsp90(N) -RJ19 was determined by X-ray diffraction (resolution limit, 2.0 angstrom, PDB code 4L90). The crystal structure of Hsp90(N)-RJ19 was analyzed in detail and compared with that of native Hsp90(N), Hsp90(N)-ATP, and Hsp90(N) -GDM, respectively. It was indicated that RJ19 interacted with Hsp90(N) at the ATP-binding pocket, which suggests that RJ19 may replace nucleotides to bind with Hsp90(N) to result in chaperone function failure of Hsp90. RJ19, therefore, has emerged as a promising anticancer lead compound. Rearrangement and displacement of L2 Loop in Hsp90(N)=-RJ19 play a key role in the function failure, which also makes the pocket wider and longer facilitating structure modification of RJ19 later. The complex crystal structure and interaction between RJ19 and Hsp90(N) provide a rational basis for the design and optimization of novel anticancer drugs.