3R91

Macrocyclic lactams as potent Hsp90 inhibitors with excellent tumor exposure and extended biomarker activity.

Summary for 3R91

• Entry DOI: 10.2210/pdb3r91/pdb
• Descriptor: Heat shock protein HSP 90-alpha, (6S)-4,6,15,15,18-pentamethyl-5,17-dioxo-2,3,4,5,6,7,14,15,16,17-decahydro-1H-12,8-(metheno)[1,4,9]triazacyclotetradecino[9,8-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: 25849.11

Authors

Zapf, C.W.,Bloom, J.D.,McBean, J.L.,Dushin, R.G.,Nittoli, T.,Otteng, M.,Ingalls, C.,Golas, J.M.,Liu, H.,Lucas, J.,Boschelli, F.,Vogan, E.,Hu, Y.,Levin, J.I. (deposition date: 2011-03-24, release date: 2011-05-11, Last modification date: 2023-09-13)

Primary citation

Zapf, C.W.,Bloom, J.D.,McBean, J.L.,Dushin, R.G.,Nittoli, T.,Otteng, M.,Ingalls, C.,Golas, J.M.,Liu, H.,Lucas, J.,Boschelli, F.,Hu, Y.,Vogan, E.,Levin, J.I.
Macrocyclic lactams as potent Hsp90 inhibitors with excellent tumor exposure and extended biomarker activity.
Bioorg.Med.Chem.Lett., 21:3411-3416, 2011

PubMed Abstract: A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. In continuation of our research in this area, macrocyclic amides and lactams were explored to reduce the risk of hERG liabilities. This effort culminated in the discovery of compound 38, which showed a favorable in vitro profile, and efficiently suppressed proliferation of several relevant cell lines. This compound showed prolonged Hsp90-inhibitory activity at least 24 h post-administration, consistent with elevated and prolonged exposure in the tumor.

PubMed: 21515049
DOI: 10.1016/j.bmcl.2011.03.112

Experimental method

X-RAY DIFFRACTION (1.579 Å)