3K98

HSP90 N-terminal domain in complex with (1R)-2-(5-chloro-2,4-dihydroxybenzoyl)-N-ethylisoindoline-1-carboxamide

Summary for 3K98

• Entry DOI: 10.2210/pdb3k98/pdb
• Related: 3K97 3K99
• Descriptor: Heat shock protein HSP 90-alpha, (1R)-2-[(5-chloro-2,4-dihydroxyphenyl)carbonyl]-N-ethyl-2,3-dihydro-1H-isoindole-1-carboxamide, PHOSPHATE ION, ... (4 entities in total)
• Functional Keywords: hsp90, atp binding domain, inhibition, acetylation, alternative splicing, atp-binding, chaperone, cytoplasm, nucleotide-binding, phosphoprotein, stress response
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : P07900
• Total number of polymer chains: 2
• Total formula weight: 53640.01

Authors

Gajiwala, K.S.,Davies II, J.F. (deposition date: 2009-10-15, release date: 2010-02-09, Last modification date: 2024-02-21)

Primary citation

Kung, P.P.,Huang, B.,Zhang, G.,Zhou, J.Z.,Wang, J.,Digits, J.A.,Skaptason, J.,Yamazaki, S.,Neul, D.,Zientek, M.,Elleraas, J.,Mehta, P.,Yin, M.J.,Hickey, M.J.,Gajiwala, K.S.,Rodgers, C.,Davies, J.F.,Gehring, M.R.
Dihydroxyphenylisoindoline amides as orally bioavailable inhibitors of the heat shock protein 90 (hsp90) molecular chaperone.
J.Med.Chem., 53:499-503, 2010

PubMed Abstract: The discovery and optimization of potency and metabolic stability of a novel class of dihyroxyphenylisoindoline amides as Hsp90 inhibitors are presented. Optimization of a screening hit using structure-based design and modification of log D and chemical structural features led to the identification of a class of orally bioavailable non-quinone-containing Hsp90 inhibitors. This class is exemplified by 14 and 15, which possess improved cell potency and pharmacokinetic profiles compared with the original screening hit.

PubMed: 19908836
DOI: 10.1021/jm901209q

Experimental method

X-RAY DIFFRACTION (2.4 Å)