Combining Hit Identification Strategies: Fragment-Based and in Silico Approaches to Orally Active 2-Aminothieno[2,3-d]pyrimidine Inhibitors of the Hsp90 Molecular Chaperone

Paul A. Brough; Xavier Barril; Jenifer Borgognoni; Patrick Chene; Nicholas G. M. Davies; Ben Davis; Martin J. Drysdale; Brian Dymock; Suzanne A. Eccles; Carlos Garcia-Echeverria; Christophe Fromont; Angela Hayes; Roderick E. Hubbard; Allan M. Jordan; Michael Rugaard Jensen; Andrew Massey; Angela Merrett; Antony Padfield; Rachel Parsons; Thomas Radimerski; Florence I. Raynaud; Alan Robertson; Stephen D. Roughley; Joseph Schoepfer; Heather Simmonite; Swee Y. Sharp; Allan Surgenor; Melanie Valenti; Steven Walls; Paul Webb; Mike Wood; Paul Workman; Lisa Wright

doi:10.1021/jm900357y

Combining Hit Identification Strategies: Fragment-Based and in Silico Approaches to Orally Active 2-Aminothieno[2,3-d]pyrimidine Inhibitors of the Hsp90 Molecular Chaperone

Paul A. Brough, Xavier Barril, Jenifer Borgognoni, Patrick Chene, Nicholas G. M. Davies, Ben Davis, Martin J. Drysdale, Brian Dymock, Suzanne A. Eccles, Carlos Garcia-Echeverria, Christophe Fromont, Angela Hayes, Roderick E. Hubbard, Allan M. Jordan, Michael Rugaard Jensen, Andrew Massey, Angela Merrett, Antony Padfield, Rachel Parsons, Thomas RadimerskiFlorence I. Raynaud, Alan Robertson, Stephen D. Roughley, Joseph Schoepfer, Heather Simmonite, Swee Y. Sharp, Allan Surgenor, Melanie Valenti, Steven Walls, Paul Webb, Mike Wood, Paul Workman, Lisa Wright

Chemistry

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

Abstract

Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of cancer. Here we describe novel 2-aminothieno[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors, which were designed by combining structural elements of distinct low affinity hits generated from fragment-based and in silico screening exercises in concert with structural information from X-ray protein crystallography. Examples from this series have high affinity (IC50 = 50-100 nM) for Hsp90 as measured in a fluorescence polarization (FP) competitive binding assay and are active in human cancer cell lines where they inhibit cell proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Several examples (34a, 34d and 34i) caused tumor growth regression at well tolerated doses when administered orally in a human BT474 human breast cancer xenograft model.

Original language	English
Pages (from-to)	4794-4809
Number of pages	16
Journal	JOURNAL OF MEDICINAL CHEMISTRY
Volume	52
Issue number	15
DOIs	https://doi.org/10.1021/jm900357y
Publication status	Published - 13 Aug 2009

Keywords

SHOCK-PROTEIN 90
POTENT ANTITUMOR-ACTIVITY
DRUG DISCOVERY
PHASE-I
HEAT-SHOCK-PROTEIN-90 INHIBITORS
MEDICINAL CHEMISTRY
ANTICANCER AGENT
TARGETING HSP90
BREAST-CANCER
ATP BINDING

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10.1021/jm900357y

http://pubs.acs.org/doi/abs/10.1021/jm900357y

Cite this

Brough, P. A., Barril, X., Borgognoni, J., Chene, P., Davies, N. G. M., Davis, B., Drysdale, M. J., Dymock, B., Eccles, S. A., Garcia-Echeverria, C., Fromont, C., Hayes, A., Hubbard, R. E., Jordan, A. M., Jensen, M. R., Massey, A., Merrett, A., Padfield, A., Parsons, R., ... Wright, L. (2009). Combining Hit Identification Strategies: Fragment-Based and in Silico Approaches to Orally Active 2-Aminothieno[2,3-d]pyrimidine Inhibitors of the Hsp90 Molecular Chaperone. JOURNAL OF MEDICINAL CHEMISTRY, 52(15), 4794-4809. https://doi.org/10.1021/jm900357y

@article{ffcad62fce714751aa30359baf711126,

title = "Combining Hit Identification Strategies: Fragment-Based and in Silico Approaches to Orally Active 2-Aminothieno[2,3-d]pyrimidine Inhibitors of the Hsp90 Molecular Chaperone",

abstract = "Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of cancer. Here we describe novel 2-aminothieno[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors, which were designed by combining structural elements of distinct low affinity hits generated from fragment-based and in silico screening exercises in concert with structural information from X-ray protein crystallography. Examples from this series have high affinity (IC50 = 50-100 nM) for Hsp90 as measured in a fluorescence polarization (FP) competitive binding assay and are active in human cancer cell lines where they inhibit cell proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Several examples (34a, 34d and 34i) caused tumor growth regression at well tolerated doses when administered orally in a human BT474 human breast cancer xenograft model.",

keywords = "SHOCK-PROTEIN 90, POTENT ANTITUMOR-ACTIVITY, DRUG DISCOVERY, PHASE-I, HEAT-SHOCK-PROTEIN-90 INHIBITORS, MEDICINAL CHEMISTRY, ANTICANCER AGENT, TARGETING HSP90, BREAST-CANCER, ATP BINDING",

author = "Brough, {Paul A.} and Xavier Barril and Jenifer Borgognoni and Patrick Chene and Davies, {Nicholas G. M.} and Ben Davis and Drysdale, {Martin J.} and Brian Dymock and Eccles, {Suzanne A.} and Carlos Garcia-Echeverria and Christophe Fromont and Angela Hayes and Hubbard, {Roderick E.} and Jordan, {Allan M.} and Jensen, {Michael Rugaard} and Andrew Massey and Angela Merrett and Antony Padfield and Rachel Parsons and Thomas Radimerski and Raynaud, {Florence I.} and Alan Robertson and Roughley, {Stephen D.} and Joseph Schoepfer and Heather Simmonite and Sharp, {Swee Y.} and Allan Surgenor and Melanie Valenti and Steven Walls and Paul Webb and Mike Wood and Paul Workman and Lisa Wright",

year = "2009",

month = aug,

day = "13",

doi = "10.1021/jm900357y",

language = "English",

volume = "52",

pages = "4794--4809",

journal = "JOURNAL OF MEDICINAL CHEMISTRY",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "15",

}

Brough, PA, Barril, X, Borgognoni, J, Chene, P, Davies, NGM, Davis, B, Drysdale, MJ, Dymock, B, Eccles, SA, Garcia-Echeverria, C, Fromont, C, Hayes, A, Hubbard, RE, Jordan, AM, Jensen, MR, Massey, A, Merrett, A, Padfield, A, Parsons, R, Radimerski, T, Raynaud, FI, Robertson, A, Roughley, SD, Schoepfer, J, Simmonite, H, Sharp, SY, Surgenor, A, Valenti, M, Walls, S, Webb, P, Wood, M, Workman, P & Wright, L 2009, 'Combining Hit Identification Strategies: Fragment-Based and in Silico Approaches to Orally Active 2-Aminothieno[2,3-d]pyrimidine Inhibitors of the Hsp90 Molecular Chaperone', JOURNAL OF MEDICINAL CHEMISTRY, vol. 52, no. 15, pp. 4794-4809. https://doi.org/10.1021/jm900357y

Combining Hit Identification Strategies: Fragment-Based and in Silico Approaches to Orally Active 2-Aminothieno[2,3-d]pyrimidine Inhibitors of the Hsp90 Molecular Chaperone. / Brough, Paul A.; Barril, Xavier; Borgognoni, Jenifer et al.
In: JOURNAL OF MEDICINAL CHEMISTRY, Vol. 52, No. 15, 13.08.2009, p. 4794-4809.

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

TY - JOUR

T1 - Combining Hit Identification Strategies

T2 - Fragment-Based and in Silico Approaches to Orally Active 2-Aminothieno[2,3-d]pyrimidine Inhibitors of the Hsp90 Molecular Chaperone

AU - Brough, Paul A.

AU - Barril, Xavier

AU - Borgognoni, Jenifer

AU - Chene, Patrick

AU - Davies, Nicholas G. M.

AU - Davis, Ben

AU - Drysdale, Martin J.

AU - Dymock, Brian

AU - Eccles, Suzanne A.

AU - Garcia-Echeverria, Carlos

AU - Fromont, Christophe

AU - Hayes, Angela

AU - Hubbard, Roderick E.

AU - Jordan, Allan M.

AU - Jensen, Michael Rugaard

AU - Massey, Andrew

AU - Merrett, Angela

AU - Padfield, Antony

AU - Parsons, Rachel

AU - Radimerski, Thomas

AU - Raynaud, Florence I.

AU - Robertson, Alan

AU - Roughley, Stephen D.

AU - Schoepfer, Joseph

AU - Simmonite, Heather

AU - Sharp, Swee Y.

AU - Surgenor, Allan

AU - Valenti, Melanie

AU - Walls, Steven

AU - Webb, Paul

AU - Wood, Mike

AU - Workman, Paul

AU - Wright, Lisa

PY - 2009/8/13

Y1 - 2009/8/13

N2 - Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of cancer. Here we describe novel 2-aminothieno[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors, which were designed by combining structural elements of distinct low affinity hits generated from fragment-based and in silico screening exercises in concert with structural information from X-ray protein crystallography. Examples from this series have high affinity (IC50 = 50-100 nM) for Hsp90 as measured in a fluorescence polarization (FP) competitive binding assay and are active in human cancer cell lines where they inhibit cell proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Several examples (34a, 34d and 34i) caused tumor growth regression at well tolerated doses when administered orally in a human BT474 human breast cancer xenograft model.

AB - Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of cancer. Here we describe novel 2-aminothieno[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors, which were designed by combining structural elements of distinct low affinity hits generated from fragment-based and in silico screening exercises in concert with structural information from X-ray protein crystallography. Examples from this series have high affinity (IC50 = 50-100 nM) for Hsp90 as measured in a fluorescence polarization (FP) competitive binding assay and are active in human cancer cell lines where they inhibit cell proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Several examples (34a, 34d and 34i) caused tumor growth regression at well tolerated doses when administered orally in a human BT474 human breast cancer xenograft model.

KW - SHOCK-PROTEIN 90

KW - POTENT ANTITUMOR-ACTIVITY

KW - DRUG DISCOVERY

KW - PHASE-I

KW - HEAT-SHOCK-PROTEIN-90 INHIBITORS

KW - MEDICINAL CHEMISTRY

KW - ANTICANCER AGENT

KW - TARGETING HSP90

KW - BREAST-CANCER

KW - ATP BINDING

UR - http://www.scopus.com/inward/record.url?scp=68549115383&partnerID=8YFLogxK

U2 - 10.1021/jm900357y

DO - 10.1021/jm900357y

M3 - Article

C2 - 19610616

SN - 0022-2623

VL - 52

SP - 4794

EP - 4809

JO - JOURNAL OF MEDICINAL CHEMISTRY

JF - JOURNAL OF MEDICINAL CHEMISTRY

IS - 15

ER -

Combining Hit Identification Strategies: Fragment-Based and in Silico Approaches to Orally Active 2-Aminothieno[2,3-d]pyrimidine Inhibitors of the Hsp90 Molecular Chaperone

Abstract

Keywords

Access to Document

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