Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Bioorg Med Chem Lett. 2013 Dec 15;23(24):6604-9. doi: 10.1016/j.bmcl.2013.10.054. Epub 2013 Nov 4.
The structure-activity relationships of T0901317 analogs were explored as RORc inverse agonists using the principles of property- and structure-based drug design. An X-ray co-crystal structure of T0901317 and RORc was obtained and provided molecular insight into why T0901317 functioned as an inverse agonist of RORc; whereas, the same ligand functioned as an agonist of FXR, LXR, and PXR. The structural data was also used to design inhibitors with improved RORc biochemical and cellular activities. The improved inhibitors possessed enhanced selectivity profiles (rationalized using the X-ray crystallographic data) against other nuclear receptors.
我们运用基于性质和基于结构的药物设计原理，研究了 T0901317 类似物作为 RORc 反向激动剂的结构-活性关系。获得了 T0901317 和 RORc 的 X 射线共晶结构，为 T0901317 为何作为 RORc 的反向激动剂而不是 FXR、LXR 和 PXR 的激动剂提供了分子见解。该结构数据还用于设计具有改善的 RORc 生化和细胞活性的抑制剂。改进的抑制剂具有针对其他核受体的更高选择性（通过 X 射线晶体学数据合理化）。
