Thermodynamic Dissection of Potency and Selectivity of Cytosolic Hsp90 Inhibitors
Thermodynamic Dissection of Potency and Selectivity of Cytosolic Hsp90 Inhibitors
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胞质 Hsp90 抑制剂的效力和选择性的热力学剖析
DOI：
10.1021/acs.jmedchem.0c01715
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发表时间：
2021
影响因子：
7.3
通讯作者：
Tsumoto Kouhei
中科院分区：
文献类型：
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作者：
Yoshimura Chihoko;Nagatoishi Satoru;Kuroda Daisuke;Kodama Yasuo;Uno Takao;Kitade Makoto;Chong-Takata Khoontee;Oshiumi Hiromi;Muraoka Hiromi;Yamashita Satoshi;Kawai Yuichi;Ohkubo Shuichi;Tsumoto Kouhei
细胞溶质Hsp 90选择性抑制剂TAS-116在临床试验中具有可接受的安全性特征和有前景的抗肿瘤活性。我们检查了TAS-116及其类似物的结合特征，以确定配体结合模式对胞质Hsp 90选择性的影响。Hsp 90和抑制剂TAS-116的共晶体结构分析表明，TAS-116与ATP结合口袋、ATP盖区和疏水口袋相互作用。竞争性等温滴定量热法分析证实，TAS-116（THS-510）的小片段停靠在盖区和疏水口袋中，而不与ATP结合口袋结合。THS-510表现出与Hsp 90 α结合的抑制作用，并选择性地抑制胞浆Hsp 90的活性。热容量的变化THS-510结合是积极的，可能是由于诱导的热休克蛋白90的构象重排。因此，我们得出结论，与Hsp 90疏水口袋的相互作用决定了TAS-116及其衍生物对细胞溶质Hsp 90亚型的效力和选择性。
The cytosolic Hsp90-selective inhibitor TAS-116 has an acceptable safety profile and promising antitumor activity in clinical trials. We examined the binding characteristics of TAS-116 and its analogs to determine the impact of the ligand binding mode on selectivity for cytosolic Hsp90. Analyses of the co-crystal structure of Hsp90 and inhibitor TAS-116 suggest that TAS-116 interacts with the ATP-binding pocket, the ATP lid region, and the hydrophobic pocket. A competitive isothermal titration calorimetry analysis confirmed that a small fragment of TAS-116 (THS-510) docks into the lid region and hydrophobic pockets without binding to the ATP-binding pocket. THS-510 exhibited enthalpy-driven binding to Hsp90α and selectively inhibited cytosolic Hsp90 activity. The heat capacity change of THS-510 binding was positive, likely due to the induced conformational rearrangement of Hsp90. Thus, we concluded that interactions with the hydrophobic pocket of Hsp90 determine potency and selectivity of TAS-116 and derivatives for the cytosolic Hsp90 isoform.