利用选择性组蛋白去乙酰化酶1/组蛋白去乙酰化酶2抑制剂（SHI-1:2）对组蛋白去乙酰化酶（HDAC）内腔进行探索。
Exploration of the internal cavity of histone deacetylase (HDAC) with selective HDAC1/HDAC2 inhibitors (SHI-1:2).
作者信息
Methot Joey L, Chakravarty Prasun K, Chenard Melissa, Close Joshua, Cruz Jonathan C, Dahlberg William K, Fleming Judith, Hamblett Christopher L, Hamill Julie E, Harrington Paul, Harsch Andreas, Heidebrecht Richard, Hughes Bethany, Jung Joon, Kenific Candia M, Kral Astrid M, Meinke Peter T, Middleton Richard E, Ozerova Nicole, Sloman David L, Stanton Matthew G, Szewczak Alexander A, Tyagarajan Sriram, Witter David J, Secrist J Paul, Miller Thomas A
机构信息
Department of Drug Design and Optimization, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
出版信息
Bioorg Med Chem Lett. 2008 Feb 1;18(3):973-8. doi: 10.1016/j.bmcl.2007.12.031. Epub 2008 Jan 7.
We report herein the initial exploration of novel selective HDAC1/HDAC2 inhibitors (SHI-1:2). Optimized SHI-1:2 structures exhibit enhanced intrinsic activity against HDAC1 and HDAC2, and are greater than 100-fold selective versus other HDACs, including HDAC3. Based on the SAR of these agents and our current understanding of the HDAC active site, we postulate that the SHI-1:2 extend the existing HDAC inhibitor pharmacophore to include an internal binding domain.
我们在此报告新型选择性组蛋白去乙酰化酶1/组蛋白去乙酰化酶2抑制剂（SHI-1:2）的初步探索。优化后的SHI-1:2结构对组蛋白去乙酰化酶1和组蛋白去乙酰化酶2表现出增强的内在活性，并且相对于包括组蛋白去乙酰化酶3在内的其他组蛋白去乙酰化酶具有大于100倍的选择性。基于这些药物的构效关系以及我们目前对组蛋白去乙酰化酶活性位点的理解，我们推测SHI-1:2扩展了现有的组蛋白去乙酰化酶抑制剂药效团，以包括一个内部结合域。
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