Hauptman-Woodward Medical Research Institute , Buffalo , New York 14203 , United States.
Department of Medicinal Chemistry , The University of Kansas , Lawrence , Kansas 66045 , United States.
J Med Chem. 2018 Apr 12;61(7):2793-2805. doi: 10.1021/acs.jmedchem.7b01608. Epub 2018 Mar 20.
Grp94 and Hsp90, the ER and cytoplasmic hsp90 paralogs, share a conserved ATP-binding pocket that has been targeted for therapeutics. Paralog-selective inhibitors may lead to drugs with fewer side effects. Here, we analyzed 1 (BnIm), a benzyl imidazole resorcinylic inhibitor, for its mode of binding. The structures of 1 bound to Hsp90 and Grp94 reveal large conformational changes in Grp94 but not Hsp90 that expose site 2, a binding pocket adjacent to the central ATP cavity that is ordinarily blocked. The Grp94:1 structure reveals a flipped pose of the resorcinylic scaffold that inserts into the exposed site 2. We exploited this flipped binding pose to develop a Grp94-selective derivative of 1. Our structural analysis shows that the ability of the ligand to insert its benzyl imidazole substituent into site 1, a different side pocket off the ATP binding cavity, is the key to exposing site 2 in Grp94.
Grp94 和 Hsp90（内质网和细胞质 hsp90 同系物）共享一个保守的 ATP 结合口袋，该口袋已成为治疗靶点。同系物选择性抑制剂可能会产生副作用更小的药物。在这里，我们分析了 1（BnIm），一种苯甲基咪唑间苯二酚抑制剂，研究其结合模式。1 与 Hsp90 和 Grp94 结合的结构揭示了 Grp94 发生了较大的构象变化，但 Hsp90 没有发生这种变化，从而暴露出紧邻中央 ATP 腔的结合口袋 2，该口袋通常被阻断。Grp94:1 结构揭示了间苯二酚支架的翻转构象，该支架插入暴露的口袋 2。我们利用这种翻转的结合构象，开发了 1 的 Grp94 选择性衍生物。我们的结构分析表明，配体将其苯甲基咪唑取代基插入口袋 1（ATP 结合腔旁边的一个不同侧袋）的能力是暴露出 Grp94 中口袋 2 的关键。
