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From Proteopedia
Hsp90 Alpha N-terminal Domain in Complex with an Inhibitor 3-Cyclohexyl-2-(6-hydroxy-1H-indazol-3-yl)-propionitrile
Structural highlights
Function[HS90A_HUMAN] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function.[1] [2] Publication Abstract from PubMedInhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of cancer. Here we describe the identification of novel small molecular weight inhibitors of Hsp90 using a fragment based approach. Fragments were selected by docking, tested in a biochemical assay and the confirmed hits were crystallized. Information gained from X-ray structures of these fragments and other chemotypes was used to drive the fragment evolution process. Optimization of these high muM binders resulted in 3-benzylindazole derivatives with significantly improved affinity and anti-proliferative effects in different human cancer cell lines. Fragment-based discovery of hydroxy-indazole-carboxamides as novel small molecule inhibitors of Hsp90.,Buchstaller HP, Eggenweiler HM, Sirrenberg C, Gradler U, Musil D, Hoppe E, Zimmermann A, Schwartz H, Marz J, Bomke J, Wegener A, Wolf M Bioorg Med Chem Lett. 2012 Jul 1;22(13):4396-403. Epub 2012 May 5. PMID:22632933[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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