Pfizer Worldwide Research and Development, La Jolla Laboratories, San Diego, CA 92121, USA.
Bioorg Med Chem Lett. 2011 Jun 15;21(12):3557-62. doi: 10.1016/j.bmcl.2011.04.130. Epub 2011 May 5.
A series of novel and potent small molecule Hsp90 inhibitors was optimized using X-ray crystal structures. These compounds bind in a deep pocket of the Hsp90 enzyme that is partially comprised by residues Asn51 and Ser52. Displacement of several water molecules observed crystallographically in this pocket using rule-based strategies led to significant improvements in inhibitor potency. An optimized inhibitor (compound 17) exhibited potent Hsp90 inhibition in ITC, biochemical, and cell-based assays (K(d)=1.3 nM, K(i)=15 nM, and cellular IC(50)=0.5 μM).
利用 X 射线晶体结构，对一系列新型强效小分子热休克蛋白 90（Hsp90）抑制剂进行了优化。这些化合物与 Hsp90 酶的一个深口袋结合，该口袋部分由残基 Asn51 和 Ser52 组成。使用基于规则的策略在该口袋中观察到的几个水分子的置换导致抑制剂效力显著提高。优化后的抑制剂（化合物 17）在 ITC、生化和基于细胞的测定中表现出很强的 Hsp90 抑制活性（K(d)=1.3 nM，K(i)=15 nM，细胞 IC(50)=0.5 μM）。
