Department of Chemistry and Biochemistry, Warren Center for Drug Discovery, The University of Notre Dame, 305 McCourtney Hall, Notre Dame, IN 46556, USA.
Department of Chemistry and Biochemistry, Warren Center for Drug Discovery, The University of Notre Dame, 305 McCourtney Hall, Notre Dame, IN 46556, USA.
Bioorg Med Chem Lett. 2024 Oct 1;111:129893. doi: 10.1016/j.bmcl.2024.129893. Epub 2024 Jul 21.
Glucose-regulated protein 94 (Grp94) is an isoform of the heat shock protein 90 kDa (Hsp90) family of molecular chaperones. Inhibiting Grp94 has been implicated for many diseases. Co-crystal structures of two generations of Grp94 inhibitors revealed the importance of investigating the ester group, which is projected into the site 2 pocket unique to Grp94. Therefore, a series of KUNG65 benzamide analogs was designed and synthesized to evaluate their impact on the affinity and selectivity for Grp94. The data demonstrated that substituents with small and saturated ring systems that contain hydrogen bond acceptors exhibited increased affinity for Grp94, whereas larger saturated ring system manifested increased selectivity for Grp94 over Hsp90α.
葡萄糖调节蛋白 94（Grp94）是热休克蛋白 90kDa（Hsp90）家族分子伴侣的同工型。抑制 Grp94 与许多疾病有关。两代 Grp94 抑制剂的共晶结构揭示了研究酯基的重要性，该酯基被投射到 Grp94 特有的位点 2 袋中。因此，设计并合成了一系列 KUNG65 苯甲酰胺类似物，以评估它们对 Grp94 亲和力和选择性的影响。数据表明，含有氢键受体的小而饱和的环系统取代基表现出对 Grp94 的更高亲和力，而较大的饱和环系统则表现出对 Grp94 相对于 Hsp90α 的更高选择性。
