Virtual ligand screening of the p300/CBP histone acetyltransferase: Identification of a selective small molecule inhibitor

Erin M. Bowers; Gai Yan; Chandrani Mukherjee; Andrew Orry; Ling Wang; Marc A. Holbert; Nicholas T. Crump; Catherine A. Hazzalin; Glen Liszczak; Hua Yuan; Cecilia Larocca; S. Adrian Saldanha; Ruben Abagyan; Yan Sun; David J. Meyers; Ronen Marmorstein; Louis C. Mahadevan; Rhoda M. Alani; Philip A. Cole

doi:10.1016/j.chembiol.2010.03.006

Virtual ligand screening of the p300/CBP histone acetyltransferase: Identification of a selective small molecule inhibitor

Erin M. Bowers, Gai Yan, Chandrani Mukherjee, Andrew Orry, Ling Wang, Marc A. Holbert, Nicholas T. Crump, Catherine A. Hazzalin, Glen Liszczak, Hua Yuan, Cecilia Larocca, S. Adrian Saldanha, Ruben Abagyan, Yan Sun, David J. Meyers, Ronen Marmorstein, Louis C. Mahadevan, Rhoda M. Alani, Philip A. Cole

School of Medicine

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

411 Scopus citations

Abstract

The histone acetyltransferase (HAT) p300/CBP is a transcriptional coactivator implicated in many gene regulatory pathways and protein acetylation events. Although p300 inhibitors have been reported, a potent, selective, and readily available active-sitedirected small molecule inhibitor is not yet known. Here we use a structure-based, in silico screening approach to identify a commercially available pyrazolone- containing small molecule p300 HAT inhibitor, C646. C646 is a competitive p300 inhibitor with a K_i of 400 nM and is selective versus other acetyltransferases. Studies on site-directed p300 HAT mutants and synthetic modifications of C646 confirm the importance of predicted interactions in conferring potency. Inhibition of histone acetylation and cell growth by C646 in cells validate its utility as a pharmacologic probe and suggest that p300/CBP HAT is a worthy anticancer target.

Original language	English (US)
Pages (from-to)	471-482
Number of pages	12
Journal	Chemistry and Biology
Volume	17
Issue number	5
DOIs	https://doi.org/10.1016/j.chembiol.2010.03.006
State	Published - 2010

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

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Bowers, E. M., Yan, G., Mukherjee, C., Orry, A., Wang, L., Holbert, M. A., Crump, N. T., Hazzalin, C. A., Liszczak, G., Yuan, H., Larocca, C., Saldanha, S. A., Abagyan, R., Sun, Y., Meyers, D. J., Marmorstein, R., Mahadevan, L. C., Alani, R. M., & Cole, P. A. (2010). Virtual ligand screening of the p300/CBP histone acetyltransferase: Identification of a selective small molecule inhibitor. Chemistry and Biology, 17(5), 471-482. https://doi.org/10.1016/j.chembiol.2010.03.006

Bowers, EM, Yan, G, Mukherjee, C, Orry, A, Wang, L, Holbert, MA, Crump, NT, Hazzalin, CA, Liszczak, G, Yuan, H, Larocca, C, Saldanha, SA, Abagyan, R, Sun, Y, Meyers, DJ, Marmorstein, R, Mahadevan, LC, Alani, RM & Cole, PA 2010, 'Virtual ligand screening of the p300/CBP histone acetyltransferase: Identification of a selective small molecule inhibitor', Chemistry and Biology, vol. 17, no. 5, pp. 471-482. https://doi.org/10.1016/j.chembiol.2010.03.006

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title = "Virtual ligand screening of the p300/CBP histone acetyltransferase: Identification of a selective small molecule inhibitor",

abstract = "The histone acetyltransferase (HAT) p300/CBP is a transcriptional coactivator implicated in many gene regulatory pathways and protein acetylation events. Although p300 inhibitors have been reported, a potent, selective, and readily available active-sitedirected small molecule inhibitor is not yet known. Here we use a structure-based, in silico screening approach to identify a commercially available pyrazolone- containing small molecule p300 HAT inhibitor, C646. C646 is a competitive p300 inhibitor with a Ki of 400 nM and is selective versus other acetyltransferases. Studies on site-directed p300 HAT mutants and synthetic modifications of C646 confirm the importance of predicted interactions in conferring potency. Inhibition of histone acetylation and cell growth by C646 in cells validate its utility as a pharmacologic probe and suggest that p300/CBP HAT is a worthy anticancer target.",

author = "Bowers, {Erin M.} and Gai Yan and Chandrani Mukherjee and Andrew Orry and Ling Wang and Holbert, {Marc A.} and Crump, {Nicholas T.} and Hazzalin, {Catherine A.} and Glen Liszczak and Hua Yuan and Cecilia Larocca and Saldanha, {S. Adrian} and Ruben Abagyan and Yan Sun and Meyers, {David J.} and Ronen Marmorstein and Mahadevan, {Louis C.} and Alani, {Rhoda M.} and Cole, {Philip A.}",

note = "Funding Information: We thank the National Institutes of Health, FAMRI Foundation, and Henry and Elaine Kaufman Foundation for support. E.M.B. is grateful for predoctoral support from the National Science Foundation. ",

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doi = "10.1016/j.chembiol.2010.03.006",

language = "English (US)",

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T1 - Virtual ligand screening of the p300/CBP histone acetyltransferase

T2 - Identification of a selective small molecule inhibitor

AU - Bowers, Erin M.

AU - Yan, Gai

AU - Mukherjee, Chandrani

AU - Orry, Andrew

AU - Wang, Ling

AU - Holbert, Marc A.

AU - Crump, Nicholas T.

AU - Hazzalin, Catherine A.

AU - Liszczak, Glen

AU - Yuan, Hua

AU - Larocca, Cecilia

AU - Saldanha, S. Adrian

AU - Abagyan, Ruben

AU - Sun, Yan

AU - Meyers, David J.

AU - Marmorstein, Ronen

AU - Mahadevan, Louis C.

AU - Alani, Rhoda M.

AU - Cole, Philip A.

N1 - Funding Information: We thank the National Institutes of Health, FAMRI Foundation, and Henry and Elaine Kaufman Foundation for support. E.M.B. is grateful for predoctoral support from the National Science Foundation.

PY - 2010

Y1 - 2010

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AB - The histone acetyltransferase (HAT) p300/CBP is a transcriptional coactivator implicated in many gene regulatory pathways and protein acetylation events. Although p300 inhibitors have been reported, a potent, selective, and readily available active-sitedirected small molecule inhibitor is not yet known. Here we use a structure-based, in silico screening approach to identify a commercially available pyrazolone- containing small molecule p300 HAT inhibitor, C646. C646 is a competitive p300 inhibitor with a Ki of 400 nM and is selective versus other acetyltransferases. Studies on site-directed p300 HAT mutants and synthetic modifications of C646 confirm the importance of predicted interactions in conferring potency. Inhibition of histone acetylation and cell growth by C646 in cells validate its utility as a pharmacologic probe and suggest that p300/CBP HAT is a worthy anticancer target.

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Virtual ligand screening of the p300/CBP histone acetyltransferase: Identification of a selective small molecule inhibitor

Abstract

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