Structure-based discovery of a new class of Hsp90 inhibitors

X  Barril; P  Brough; M  Drysdale; R E  Hubbard; A  Massey; A  Surgenor; L  Wright

doi:10.1016/j.bmcl.2005.08.092

Structure-based discovery of a new class of Hsp90 inhibitors

X Barril, P Brough, M Drysdale, R E Hubbard, A Massey, A Surgenor, L Wright

Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

Docking-based virtual screening identified 1-(2-phenol)-2-naphthol compounds as a new class of Hsp90 inhibitors of low to sub-micromolar potency. Here we report the binding affinities and cellular activities of several members of this class. A high resolution crystal structure of the most potent compound reveals its binding mode in the ATP binding site of Hsp90, providing a rationale for the observed activity of the series and suggesting strategies for developing compounds with improved properties. (c) 2005 Elsevier Ltd. All rights reserved.

Original language	English
Pages (from-to)	5187-5191
Number of pages	5
Journal	Bioorganic & Medicinal Chemistry Letters
Volume	15
Issue number	23
DOIs	https://doi.org/10.1016/j.bmcl.2005.08.092
Publication status	Published - 1 Dec 2005

Keywords

Hsp90 inhibitor
docking
virtual screening
hit identification
phenol-naphthol
bis-phenol
structure-based drug discovery
MOLECULAR CHAPERONE HSP90
ONCOGENIC TRANSFORMATION
CRYSTAL-STRUCTURE
PROTEIN MODELS
CANCER
GELDANAMYCIN
REFINEMENT
RADICICOL
COMPLEX

Access to Document

10.1016/j.bmcl.2005.08.092

Cite this

@article{70208d841e0447d5ba7fb488eefc4646,

title = "Structure-based discovery of a new class of Hsp90 inhibitors",

abstract = "Docking-based virtual screening identified 1-(2-phenol)-2-naphthol compounds as a new class of Hsp90 inhibitors of low to sub-micromolar potency. Here we report the binding affinities and cellular activities of several members of this class. A high resolution crystal structure of the most potent compound reveals its binding mode in the ATP binding site of Hsp90, providing a rationale for the observed activity of the series and suggesting strategies for developing compounds with improved properties. (c) 2005 Elsevier Ltd. All rights reserved.",

keywords = "Hsp90 inhibitor, docking, virtual screening, hit identification, phenol-naphthol, bis-phenol, structure-based drug discovery, MOLECULAR CHAPERONE HSP90, ONCOGENIC TRANSFORMATION, CRYSTAL-STRUCTURE, PROTEIN MODELS, CANCER, GELDANAMYCIN, REFINEMENT, RADICICOL, COMPLEX",

author = "X Barril and P Brough and M Drysdale and Hubbard, {R E} and A Massey and A Surgenor and L Wright",

year = "2005",

month = dec,

day = "1",

doi = "10.1016/j.bmcl.2005.08.092",

language = "English",

volume = "15",

pages = "5187--5191",

journal = "Bioorganic & Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier",

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TY - JOUR

T1 - Structure-based discovery of a new class of Hsp90 inhibitors

AU - Barril, X

AU - Brough, P

AU - Drysdale, M

AU - Hubbard, R E

AU - Massey, A

AU - Surgenor, A

AU - Wright, L

PY - 2005/12/1

Y1 - 2005/12/1

N2 - Docking-based virtual screening identified 1-(2-phenol)-2-naphthol compounds as a new class of Hsp90 inhibitors of low to sub-micromolar potency. Here we report the binding affinities and cellular activities of several members of this class. A high resolution crystal structure of the most potent compound reveals its binding mode in the ATP binding site of Hsp90, providing a rationale for the observed activity of the series and suggesting strategies for developing compounds with improved properties. (c) 2005 Elsevier Ltd. All rights reserved.

AB - Docking-based virtual screening identified 1-(2-phenol)-2-naphthol compounds as a new class of Hsp90 inhibitors of low to sub-micromolar potency. Here we report the binding affinities and cellular activities of several members of this class. A high resolution crystal structure of the most potent compound reveals its binding mode in the ATP binding site of Hsp90, providing a rationale for the observed activity of the series and suggesting strategies for developing compounds with improved properties. (c) 2005 Elsevier Ltd. All rights reserved.

KW - Hsp90 inhibitor

KW - docking

KW - virtual screening

KW - hit identification

KW - phenol-naphthol

KW - bis-phenol

KW - structure-based drug discovery

KW - MOLECULAR CHAPERONE HSP90

KW - ONCOGENIC TRANSFORMATION

KW - CRYSTAL-STRUCTURE

KW - PROTEIN MODELS

KW - CANCER

KW - GELDANAMYCIN

KW - REFINEMENT

KW - RADICICOL

KW - COMPLEX

U2 - 10.1016/j.bmcl.2005.08.092

DO - 10.1016/j.bmcl.2005.08.092

M3 - Article

SN - 0960-894X

VL - 15

SP - 5187

EP - 5191

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

IS - 23

ER -