Exploiting protein conformational change to optimize adenosine-derived inhibitors of HSP70

Matthew D. Cheeseman; Isaac M. Westwood; Olivier Barbeau; Martin Rowlands; Sarah Dobson; Alan M. Jones; Fiona Jeganathan; Rosemary Burke; Nadia Kadi; Paul Workman; Ian Collins; Rob L M Van Montfort; Keith Jones

doi:10.1021/acs.jmedchem.5b02001

Exploiting protein conformational change to optimize adenosine-derived inhibitors of HSP70

Matthew D. Cheeseman, Isaac M. Westwood, Olivier Barbeau, Martin Rowlands, Sarah Dobson, Alan M. Jones, Fiona Jeganathan, Rosemary Burke, Nadia Kadi, Paul Workman, Ian Collins, Rob L M Van Montfort, Keith Jones

Pharmacy

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

19 Citations (Scopus)

Abstract

HSP70 is a molecular chaperone and a key component of the heat-shock response. Because of its proposed importance in oncology, this protein has become a popular target for drug discovery, efforts which have as yet brought little success. This study demonstrates that adenosine-derived HSP70 inhibitors potentially bind to the protein with a novel mechanism of action, the stabilization by desolvation of an intramolecular salt-bridge which induces a conformational change in the protein, leading to high affinity ligands. We also demonstrate that through the application of this mechanism, adenosine-derived HSP70 inhibitors can be optimized in a rational manner.

Original language	English
Pages (from-to)	4625-4636
Number of pages	12
Journal	Journal of Medicinal Chemistry
Volume	59
Issue number	10
Early online date	27 Apr 2016
DOIs	https://doi.org/10.1021/acs.jmedchem.5b02001
Publication status	Published - 26 May 2016

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Cheeseman, M. D., Westwood, I. M., Barbeau, O., Rowlands, M., Dobson, S., Jones, A. M., Jeganathan, F., Burke, R., Kadi, N., Workman, P., Collins, I., Van Montfort, R. L. M., & Jones, K. (2016). Exploiting protein conformational change to optimize adenosine-derived inhibitors of HSP70. Journal of Medicinal Chemistry, 59(10), 4625-4636. https://doi.org/10.1021/acs.jmedchem.5b02001

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author = "Cheeseman, {Matthew D.} and Westwood, {Isaac M.} and Olivier Barbeau and Martin Rowlands and Sarah Dobson and Jones, {Alan M.} and Fiona Jeganathan and Rosemary Burke and Nadia Kadi and Paul Workman and Ian Collins and {Van Montfort}, {Rob L M} and Keith Jones",

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Cheeseman, MD, Westwood, IM, Barbeau, O, Rowlands, M, Dobson, S, Jones, AM, Jeganathan, F, Burke, R, Kadi, N, Workman, P, Collins, I, Van Montfort, RLM & Jones, K 2016, 'Exploiting protein conformational change to optimize adenosine-derived inhibitors of HSP70', Journal of Medicinal Chemistry, vol. 59, no. 10, pp. 4625-4636. https://doi.org/10.1021/acs.jmedchem.5b02001

TY - JOUR

T1 - Exploiting protein conformational change to optimize adenosine-derived inhibitors of HSP70

AU - Cheeseman, Matthew D.

AU - Westwood, Isaac M.

AU - Barbeau, Olivier

AU - Rowlands, Martin

AU - Dobson, Sarah

AU - Jones, Alan M.

AU - Jeganathan, Fiona

AU - Burke, Rosemary

AU - Kadi, Nadia

AU - Workman, Paul

AU - Collins, Ian

AU - Van Montfort, Rob L M

AU - Jones, Keith

PY - 2016/5/26

Y1 - 2016/5/26

N2 - HSP70 is a molecular chaperone and a key component of the heat-shock response. Because of its proposed importance in oncology, this protein has become a popular target for drug discovery, efforts which have as yet brought little success. This study demonstrates that adenosine-derived HSP70 inhibitors potentially bind to the protein with a novel mechanism of action, the stabilization by desolvation of an intramolecular salt-bridge which induces a conformational change in the protein, leading to high affinity ligands. We also demonstrate that through the application of this mechanism, adenosine-derived HSP70 inhibitors can be optimized in a rational manner.

AB - HSP70 is a molecular chaperone and a key component of the heat-shock response. Because of its proposed importance in oncology, this protein has become a popular target for drug discovery, efforts which have as yet brought little success. This study demonstrates that adenosine-derived HSP70 inhibitors potentially bind to the protein with a novel mechanism of action, the stabilization by desolvation of an intramolecular salt-bridge which induces a conformational change in the protein, leading to high affinity ligands. We also demonstrate that through the application of this mechanism, adenosine-derived HSP70 inhibitors can be optimized in a rational manner.

UR - http://www.mendeley.com/research/exploiting-protein-conformational-change-optimize-adenosinederived-inhibitors-hsp70

U2 - 10.1021/acs.jmedchem.5b02001

DO - 10.1021/acs.jmedchem.5b02001

M3 - Article

C2 - 27119979

SN - 0022-2623

VL - 59

SP - 4625

EP - 4636

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 10

ER -

Exploiting protein conformational change to optimize adenosine-derived inhibitors of HSP70

Abstract

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