Novel, potent small-molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design

B W  Dymock; X  Barril; P A  Brough; J E  Cansfield; A  Massey; E  McDonald; R E  Hubbard; A  Surgenor; S D  Roughley; P  Webb; P  Workman; L  Wright; M J  Drysdale

doi:10.1021/jm050355

Novel, potent small-molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design

B W Dymock, X Barril, P A Brough, J E Cansfield, A Massey, E McDonald, R E Hubbard, A Surgenor, S D Roughley, P Webb, P Workman, L Wright, M J Drysdale

Chemistry

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

Abstract

The crystal structure of a previously reported screening hit 1 (CCT018159) bound to the N terminal domain of molecular chaperone Hsp90 has been used to design 5-amide analogues. These exhibit enhanced potency against the target in binding and functional assays with accompanying appropriate cellular pharmaeodynamic changes. Compound 11 (VER-49009) compares favorably with the clinically evaluated 17-AAG.

Original language	English
Pages (from-to)	4212-4215
Number of pages	4
Journal	JOURNAL OF MEDICINAL CHEMISTRY
Volume	48
Issue number	13
DOIs	https://doi.org/10.1021/jm050355
Publication status	Published - 30 Jun 2005

Keywords

TISSUE DISTRIBUTION
PHARMACOKINETICS
DERIVATIVES
RADICICOL
BINDING
CANCER

Access to Document

10.1021/jm050355

Cite this

Dymock, B. W., Barril, X., Brough, P. A., Cansfield, J. E., Massey, A., McDonald, E., Hubbard, R. E., Surgenor, A., Roughley, S. D., Webb, P., Workman, P., Wright, L., & Drysdale, M. J. (2005). Novel, potent small-molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design. JOURNAL OF MEDICINAL CHEMISTRY, 48(13), 4212-4215. https://doi.org/10.1021/jm050355

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abstract = "The crystal structure of a previously reported screening hit 1 (CCT018159) bound to the N terminal domain of molecular chaperone Hsp90 has been used to design 5-amide analogues. These exhibit enhanced potency against the target in binding and functional assays with accompanying appropriate cellular pharmaeodynamic changes. Compound 11 (VER-49009) compares favorably with the clinically evaluated 17-AAG.",

keywords = "TISSUE DISTRIBUTION, PHARMACOKINETICS, DERIVATIVES, RADICICOL, BINDING, CANCER",

author = "Dymock, {B W} and X Barril and Brough, {P A} and Cansfield, {J E} and A Massey and E McDonald and Hubbard, {R E} and A Surgenor and Roughley, {S D} and P Webb and P Workman and L Wright and Drysdale, {M J}",

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Dymock, BW, Barril, X, Brough, PA, Cansfield, JE, Massey, A, McDonald, E, Hubbard, RE, Surgenor, A, Roughley, SD, Webb, P, Workman, P, Wright, L & Drysdale, MJ 2005, 'Novel, potent small-molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design', JOURNAL OF MEDICINAL CHEMISTRY, vol. 48, no. 13, pp. 4212-4215. https://doi.org/10.1021/jm050355

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T1 - Novel, potent small-molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design

AU - Dymock, B W

AU - Barril, X

AU - Brough, P A

AU - Cansfield, J E

AU - Massey, A

AU - McDonald, E

AU - Hubbard, R E

AU - Surgenor, A

AU - Roughley, S D

AU - Webb, P

AU - Workman, P

AU - Wright, L

AU - Drysdale, M J

PY - 2005/6/30

Y1 - 2005/6/30

N2 - The crystal structure of a previously reported screening hit 1 (CCT018159) bound to the N terminal domain of molecular chaperone Hsp90 has been used to design 5-amide analogues. These exhibit enhanced potency against the target in binding and functional assays with accompanying appropriate cellular pharmaeodynamic changes. Compound 11 (VER-49009) compares favorably with the clinically evaluated 17-AAG.

AB - The crystal structure of a previously reported screening hit 1 (CCT018159) bound to the N terminal domain of molecular chaperone Hsp90 has been used to design 5-amide analogues. These exhibit enhanced potency against the target in binding and functional assays with accompanying appropriate cellular pharmaeodynamic changes. Compound 11 (VER-49009) compares favorably with the clinically evaluated 17-AAG.

KW - TISSUE DISTRIBUTION

KW - PHARMACOKINETICS

KW - DERIVATIVES

KW - RADICICOL

KW - BINDING

KW - CANCER

U2 - 10.1021/jm050355

DO - 10.1021/jm050355

M3 - Article

SN - 0022-2623

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