4-Amino derivatives of the Hsp90 inhibitor CCT018159

Xavier Barril; Mandy C Beswick; Adam Collier; Martin J Drysdale; Brian W Dymock; Alexandra Fink; Kate Grant; Robert Howes; Allan M Jordan; Andrew Massey; Allan Surgenor; Joanne Wayne; Paul Workman; Lisa Wright

doi:10.1016/j.bmcl.2006.01.099

4-Amino derivatives of the Hsp90 inhibitor CCT018159

Xavier Barril, Mandy C Beswick, Adam Collier, Martin J Drysdale, Brian W Dymock, Alexandra Fink, Kate Grant, Robert Howes, Allan M Jordan, Andrew Massey, Allan Surgenor, Joanne Wayne, Paul Workman, Lisa Wright

Cancer Research UK Manchester Institute

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

Abstract

Novel piperazinyl, morpholino and piperidyl derivatives of the pyrazole-based Hsp90 inhibitor CCT018159 are described. Structure-activity relationships have been elucidated by X-ray co-crystal analysis of the new compounds bound to the N-terminal domain of human Hsp90. Key features of the binding mode are essentially identical to the recently reported potent analogue VER-49009. The most potent of the new compounds has a methylsulfonylbenzyl substituent appended to the piperazine nitrogen, possesses an IC50 of less than 600 nM binding against the enzyme and demonstrates low micromolar inhibition of tumour cell proliferation.

Original language	English
Pages (from-to)	2543-8
Number of pages	6
Journal	Bioorg. Med. Chem. Lett.
Volume	16
Issue number	9
DOIs	https://doi.org/10.1016/j.bmcl.2006.01.099
Publication status	Published - 1 May 2006

Keywords

Binding Sites
Crystallography, X-Ray
HSP90 Heat-Shock Proteins
Heterocyclic Compounds, 2-Ring
Humans
Models, Molecular
Molecular Structure
Pyrazoles
Structure-Activity Relationship

Research Beacons, Institutes and Platforms

Manchester Cancer Research Centre

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmcl.2006.01.099

Cite this

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title = "4-Amino derivatives of the Hsp90 inhibitor CCT018159",

abstract = "Novel piperazinyl, morpholino and piperidyl derivatives of the pyrazole-based Hsp90 inhibitor CCT018159 are described. Structure-activity relationships have been elucidated by X-ray co-crystal analysis of the new compounds bound to the N-terminal domain of human Hsp90. Key features of the binding mode are essentially identical to the recently reported potent analogue VER-49009. The most potent of the new compounds has a methylsulfonylbenzyl substituent appended to the piperazine nitrogen, possesses an IC50 of less than 600 nM binding against the enzyme and demonstrates low micromolar inhibition of tumour cell proliferation.",

keywords = "Binding Sites, Crystallography, X-Ray, HSP90 Heat-Shock Proteins, Heterocyclic Compounds, 2-Ring, Humans, Models, Molecular, Molecular Structure, Pyrazoles, Structure-Activity Relationship",

author = "Xavier Barril and Beswick, \{Mandy C\} and Adam Collier and Drysdale, \{Martin J\} and Dymock, \{Brian W\} and Alexandra Fink and Kate Grant and Robert Howes and Jordan, \{Allan M\} and Andrew Massey and Allan Surgenor and Joanne Wayne and Paul Workman and Lisa Wright",

year = "2006",

month = may,

day = "1",

doi = "10.1016/j.bmcl.2006.01.099",

language = "English",

volume = "16",

pages = "2543--8",

journal = "Bioorg. Med. Chem. Lett.",

issn = "0960-894X",

publisher = "Elsevier BV",

number = "9",

}

TY - JOUR

T1 - 4-Amino derivatives of the Hsp90 inhibitor CCT018159

AU - Barril, Xavier

AU - Beswick, Mandy C

AU - Collier, Adam

AU - Drysdale, Martin J

AU - Dymock, Brian W

AU - Fink, Alexandra

AU - Grant, Kate

AU - Howes, Robert

AU - Jordan, Allan M

AU - Massey, Andrew

AU - Surgenor, Allan

AU - Wayne, Joanne

AU - Workman, Paul

AU - Wright, Lisa

PY - 2006/5/1

Y1 - 2006/5/1

N2 - Novel piperazinyl, morpholino and piperidyl derivatives of the pyrazole-based Hsp90 inhibitor CCT018159 are described. Structure-activity relationships have been elucidated by X-ray co-crystal analysis of the new compounds bound to the N-terminal domain of human Hsp90. Key features of the binding mode are essentially identical to the recently reported potent analogue VER-49009. The most potent of the new compounds has a methylsulfonylbenzyl substituent appended to the piperazine nitrogen, possesses an IC50 of less than 600 nM binding against the enzyme and demonstrates low micromolar inhibition of tumour cell proliferation.

AB - Novel piperazinyl, morpholino and piperidyl derivatives of the pyrazole-based Hsp90 inhibitor CCT018159 are described. Structure-activity relationships have been elucidated by X-ray co-crystal analysis of the new compounds bound to the N-terminal domain of human Hsp90. Key features of the binding mode are essentially identical to the recently reported potent analogue VER-49009. The most potent of the new compounds has a methylsulfonylbenzyl substituent appended to the piperazine nitrogen, possesses an IC50 of less than 600 nM binding against the enzyme and demonstrates low micromolar inhibition of tumour cell proliferation.

KW - Binding Sites

KW - Crystallography, X-Ray

KW - HSP90 Heat-Shock Proteins

KW - Heterocyclic Compounds, 2-Ring

KW - Humans

KW - Models, Molecular

KW - Molecular Structure

KW - Pyrazoles

KW - Structure-Activity Relationship

UR - https://www.scopus.com/pages/publications/33645002986

U2 - 10.1016/j.bmcl.2006.01.099

DO - 10.1016/j.bmcl.2006.01.099

M3 - Article

C2 - 16480864

SN - 0960-894X

VL - 16

SP - 2543

EP - 2548

JO - Bioorg. Med. Chem. Lett.

JF - Bioorg. Med. Chem. Lett.

IS - 9

ER -

4-Amino derivatives of the Hsp90 inhibitor CCT018159

Abstract

Keywords

Research Beacons, Institutes and Platforms

UN SDGs

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