3RKZ

Discovery of a stable macrocyclic o-aminobenzamide Hsp90 inhibitor capable of significantly decreasing tumor volume in a mouse xenograft model.

Summary for 3RKZ

• Entry DOI: 10.2210/pdb3rkz/pdb
• Descriptor: Heat shock protein HSP 90-alpha, (5R,6S)-3-(L-alanyl)-5,6,15,15,18-pentamethyl-17-oxo-2,3,4,5,6,7,14,15,16,17-decahydro-1H-12,8-(metheno)[1,5,9]triazacyclotetradecino[1,2-a]indole-9-carboxamide (3 entities in total)
• Functional Keywords: chaperone, atp binding domain, atp-binding, nucleotide-binding, phosphoprotein, stress response, chaperone-chaperone inhibitor complex, chaperone/chaperone inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P07900
• Total number of polymer chains: 1
• Total formula weight: 25906.21

Authors

Zapf, C.W.,Bloom, J.D.,Li, Z.,Dushin, R.G.,Nittoli, T.,Otteng, M.,Nikitenko, A.,Golas, J.M.,Liu, H.,Lucas, J.,Boschelli, F.,Vogan, E.,Olland, A.,Johnson, M.,Levin, J.I. (deposition date: 2011-04-18, release date: 2011-07-13, Last modification date: 2023-09-13)

Primary citation

Zapf, C.W.,Bloom, J.D.,Li, Z.,Dushin, R.G.,Nittoli, T.,Otteng, M.,Nikitenko, A.,Golas, J.M.,Liu, H.,Lucas, J.,Boschelli, F.,Vogan, E.,Olland, A.,Johnson, M.,Levin, J.I.
Discovery of a stable macrocyclic o-aminobenzamide Hsp90 inhibitor which significantly decreases tumor volume in a mouse xenograft model.
Bioorg.Med.Chem.Lett., 21:4602-4607, 2011

PubMed Abstract: An extension of our previously reported series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. Addition of a second methyl group to the tether provided analogs that show increased potency in binding as well as cell-proliferation assays and, more importantly, are stable toward microsomes. We wish to disclose the discovery of a macrocycle which showed impressive biomarker activity 24-h post dosing and which demonstrated prolonged exposure in tumors. When studied in a lung cancer xenograft model, the compound demonstrated significant tumor size reduction.

PubMed: 21715165
DOI: 10.1016/j.bmcl.2011.05.102

Experimental method

X-RAY DIFFRACTION (1.5693 Å)