3R92

Discovery of a macrocyclic o-aminobenzamide Hsp90 inhibitor with heterocyclic tether that shows extended biomarker activity and in vivo efficacy in a mouse xenograft model.

3R92 の概要

• エントリーDOI: 10.2210/pdb3r92/pdb
• 分子名称: Heat shock protein HSP 90-alpha, (3aR)-13,13,16-trimethyl-15-oxo-1,2,3,3a,4,5,12,14,15,17,18,19-dodecahydro-13H-10,6-(metheno)pyrrolo[2',1':3,4][1,4,9]triazacyclotetradecino[9,8-a]indole-7-carboxamide (3 entities in total)
• 機能のキーワード: chaperone, atp binding domain, atp-binding, nucleotide-binding, phosphoprotein, stress response, chaperone-chaperone inhibitor complex, chaperone/chaperone inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 25847.14

構造登録者

Zapf, C.W.,Bloom, J.D.,McBean, J.L.,Dushin, R.G.,Golas, J.M.,Liu, H.,Lucas, J.,Boschelli, F.,Vogan, E.M.,Levin, J.I. (登録日: 2011-03-24, 公開日: 2011-06-08, 最終更新日: 2024-02-21)

主引用文献

Zapf, C.W.,Bloom, J.D.,McBean, J.L.,Dushin, R.G.,Golas, J.M.,Liu, H.,Lucas, J.,Boschelli, F.,Vogan, E.,Levin, J.I.
Discovery of a macrocyclic o-aminobenzamide Hsp90 inhibitor with heterocyclic tether that shows extended biomarker activity and in vivo efficacy in a mouse xenograft model.
Bioorg.Med.Chem.Lett., 21:3627-3631, 2011

PubMed Abstract: A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. In continuation of our research, heterocycle-containing tethers were explored with the intent to further improve potency and minimize hERG liabilities. This effort culminated in the discovery of compound 10, which efficiently suppressed proliferation of HCT116 and U87 cells. This compound showed prolonged Hsp90-inhibitory activity at least 24h post-administration consistent with elevated and prolonged exposure in the tumor. When studied in a xenograft model, the compound demonstrated significant suppression of tumor growth.

PubMed: 21605975
DOI: 10.1016/j.bmcl.2011.04.102

実験手法

X-RAY DIFFRACTION (1.5801 Å)