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J Med Chem ; 64(5): 2669-2677, 2021 03 11.
Artículo en Inglés | MEDLINE | ID: mdl-33621080

RESUMEN

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.


Asunto(s)
Antineoplásicos/metabolismo , Benzamidas/metabolismo , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Pirazoles/metabolismo , Sitios de Unión , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Unión Proteica , Termodinámica
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