Development of Phenyl Cyclohexylcarboxamides as a Novel Class of Hsp90 C-terminal Inhibitors.
Development of Phenyl Cyclohexylcarboxamides as a Novel Class of Hsp90 C-terminal Inhibitors.
复制标题
DOI：
10.1002/chem.201703206
复制
发表时间：
2017-11-21
期刊：
影响因子：
--
通讯作者：
Blagg BSJ
中科院分区：
文献类型：
--
作者：
Garg G;Forsberg LK;Zhao H;Blagg BSJ
抑制热休克蛋白90（Hsp 90）C-末端代表了用于治疗癌症的有前景的治疗策略。Novobiocin是一种香豆素类抗生素，是第一个发现的Hsp 90 C-末端抑制剂，但其抗增殖活性较差（SKBr 3，IC 50 ~ 700 μM）。随后对新生霉素的SAR研究导致开发了几种类似物，这些类似物对几种癌细胞系表现出改善的抗增殖活性。最近，我们证明了联苯核可以用来代替香豆素环系统，这导致了更有效的类似物。在先前努力的延续中，本文所述的工作已经鉴定了苯基环己基核心作为Hsp 90 C-末端抑制的新型支架。对该支架的SAR研究导致开发了通过Hsp 90抑制对SKBr 3和MCF-7乳腺癌细胞系表现出中纳摩尔活性的化合物。骨架优化：探索中心核心以鉴定用于Hsp 90 C-末端抑制的优化支架。结构研究导致开发苯基环己基甲酰胺作为一类新的热休克蛋白90 C-末端抑制剂。这种新的支架具有改善的生物活性，并为未来的Hsp 90抑制剂提供了新的模板。
Inhibition of the heat shock protein 90 (Hsp90) C-terminus represents a promising therapeutic strategy for the treatment of cancer. Novobiocin, a coumarin antibiotic, was the first Hsp90 C-terminal inhibitor identified, however, it manifested poor anti-proliferative activity (SKBr3, IC50 ~ 700 μM). Subsequent SAR studies on novobiocin led to development of several analogues that exhibited improved anti-proliferative activity against several cancer cell lines. Recently, we demonstrated that the biphenyl core could be used in lieu of the coumarin ring system, which resulted in more efficacious analogues. In continuation of previous efforts, the work described herein has identified the phenyl cyclohexyl core as a novel scaffold for Hsp90 C-terminal inhibition. SAR studies on this scaffold led to the development of compounds that manifest mid-nanomolar activity against SKBr3 and MCF-7 breast cancer cell lines through Hsp90 inhibition. Backbone optimization: The central core was explored to identify an optimized scaffold for Hsp90 C-terminal inhibition. Structural investigations led to the development of phenyl cyclohexyl carboxamides as a novel class of Hsp90 C-terminal inhibitors. This new scaffold exhibits improved biological activity and provides a new template for future Hsp90 inhibitors.
登录
查看更多内容
DOI：
10.1002/chem.201504955
发表时间：
2016-05-10
期刊：
Chemistry (Weinheim an der Bergstrasse, Germany)
影响因子：
--
作者：
Byrd KM;Subramanian C;Sanchez J;Motiwala HF;Liu W;Cohen MS;Holzbeierlein J;Blagg BS
通讯作者：
Blagg BS
影响因子：
3.6
作者：
Donnelly, Alison C.;Mays, Jared R.;Burlison, Joseph A.;Nelson, John T.;Vielhauer, George;Holzbeierlein, Jeffrey;Blagg, Brian S. J.
通讯作者：
Blagg, Brian S. J.
DOI：
10.1158/1078-0432.ccr-11-1000
发表时间：
2012-01-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Neckers L;Workman P
通讯作者：
Workman P
影响因子：
4.8
作者：
Marcu, MG;Chadli, A;Neckers, LM
通讯作者：
Neckers, LM
影响因子：
7.3
作者：
Lovering, Frank;Bikker, Jack;Humblet, Christine
通讯作者：
Humblet, Christine