Chemistry & Biology
p300/CBP HAT Inhibition
the Johns Hopkins Flow Cytometry Core Facility. Data acquisition and analysis
were performed with the CellQuest software (BD). WinMDI 2.9 (http://facs.
Edmunds, J.W., Mahadevan, L.C., and Clayton, A.L. (2008). Dynamic histone
H3 methylation during gene induction: HYPB/Setd2 mediates all H3K36 trime-
thylation. EMBO J. 27, 406–420.
Feng, B.Y., Shelat, A., Doman, T.N., Guy, R.K., and Shoichet, B.K. (2005).
High-throughput assays for promiscuous inhibitors. Nat. Chem. Biol. 1,
146–148.
SUPPLEMENTAL INFORMATION
Goodman, R.H., and Smolik, S. (2000). CBP/p300 in cell growth, transforma-
Supplemental information includes four figures, two tables, and nine
tion, and development. Genes Dev. 14, 1553–1577.
Gu, W., and Roeder, R.G. (1997). Activation of p53 sequence-specific DNA
binding by acetylation of the p53 C-terminal domain. Cell 90, 595–606.
Guidez, F., Howell, L., Isalan, M., Cebrat, M., Alani, R.M., Ivins, S., Hormaeche,
I., McConnell, M.J., Pierce, S., Cole, P.A., et al. (2005). Histone acetyltransfer-
ase activity of p300 is required for transcriptional repression by the promyelo-
cytic leukemia zinc finger protein. Mol. Cell. Biol. 25, 5552–5566.
ACKNOWLEDGMENTS
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.
Haberland, M., Montgomery, R.L., and Olson, E.N. (2009). The many roles of
histone deacetylases in development and physiology: implications for disease
and therapy. Nat. Rev. Genet. 10, 32–42.
Received: December 23, 2009
Revised: February 18, 2010
Accepted: March 4, 2010
Published: May 27, 2010
Halgren, T.A., and Nachbar, R.B. (1996). Merck molecular force field. IV.
Conformational energies and geometries for MMFF94. J. Comput. Chem.
17, 587–615.
Hodawadekar, S.C., and Marmorstein, R. (2007). Chemistry of acetyl transfer
by histone modifying enzymes: structure, mechanism and implications for
effector design. Oncogene 26, 5528–5540.
REFERENCES
Abagyan, R., Totrov, M., and Kuznetsov, D. (1994). ICM—a new method for
protein modeling and design: applications to docking and structure prediction
from the distorted native conformation. J. Comput. Chem. 15, 488–506.
Hodgkiss, R.J., Begg, A.C., Middleton, R.W., Parrick, J., Stratford, M.R.,
Wardman, P., and Wilson, G.D. (1991). Fluorescent markers for hypoxic cells.
A study of novel heterocyclic compounds that undergo bio-reductive binding.
Biochem. Pharmacol. 41, 533–541.
Arif, M., Pradhan, S.K., Thanuja, G.R., Vedamurthy, B.M., Agrawal, S.,
Dasgupta, D., and Kundu, T.K. (2009). Mechanism of p300 specific histone
acetyltransferase inhibition by small molecules. J. Med. Chem. 52, 267–277.
Holbert, M.A., Sikorski, T., Carten, J., Snowflack, D., Hodawadekar, S., and
Marmorstein, R. (2007). The human monocytic leukemia zinc finger histone
acetyltransferase domain contains DNA-binding activity implicated in chro-
matin targeting. J. Biol. Chem. 282, 36603–36613.
Balasubramanyam, K., Swaminathan, V., Ranganathan, A., and Kundu, T.K.
(2003). Small molecule modulators of histone acetyltransferase p300. J. Biol.
Chem. 278, 19134–19140.
Hosoya, T., Aoyama, H., Ikemoto, T., Kihara, Y., Hiramatsu, T., Endoc, M., and
Suzuki, M. (2003). Dantrolene analogues revisited: General synthesis and
specific functions capable of discriminating two kinds of Ca2+ release from
sarcoplasmic reticulum of mouse skeletal muscle. Bioorg. Med. Chem. 11,
663–673.
Balasubramanyam, K., Varier, R.A., Altaf, M., Swaminathan, V., Siddappa,
N.B., Ranga, U., and Kundu, T.K. (2004). Curcumin, a novel p300/CREB-
binding protein-specific inhibitor of acetyltransferase, represses the acetyla-
tion of histone/nonhistone proteins and histone acetyltransferase-dependent
chromatin transcription. J. Biol. Chem. 279, 51163–51171.
Itoh, Y., Suzuki, T., and Miyata, N. (2008). Isoform-selective histone deacety-
lase inhibitors. Curr. Pharm. Des. 14, 529–544.
Bannister, A.J., and Kouzarides, T. (1996). The CBP co-activator is a histone
Iyer, N.G., Xian, J., Chin, S.F., Bannister, A.J., Daigo, Y., Aparicio, S., Kouzar-
ides, T., and Caldas, C. (2007). p300 is required for orderly G1/S transition in
human cancer cells. Oncogene 26, 21–29.
acetyltransferase. Nature 384, 641–643.
Bisson, W.H., Koch, D.C., O’Donnell, E.F., Khalil, S.M., Kerkvliet, N.I.,
Tanguay, R.L., Abagyan, R., and Kolluri, S.K. (2009). Modeling of the aryl
hydrocarbon receptor (AhR) ligand binding domain and its utility in virtual
ligand screening to predict new AhR ligands. J. Med. Chem. 52, 5635–5641.
Kim, J.B., and Lee, Y.-S. (1991). Peptide synthesis with polymer bound active
ester. II Synthesis of pyrazolone resin and its applications in acylation reaction.
Bull. Korean Chem. Soc. 12, 376–379.
Cavasotto, C.N., Orry, A.J., Murgolo, N.J., Czarniecki, M.F., Kocsi, S.A.,
Hawes, B.E., O’Neill, K.A., Hine, H., Burton, M.S., Voigt, J.H., et al. (2008).
Discovery of novel chemotypes to a G-protein-coupled receptor through
ligand-steered homology modeling and structure-based virtual screening.
J. Med. Chem. 51, 581–588.
Kim, Y., Tanner, K.G., and Denu, J.M. (2000). A continuous, nonradioactive
assay for histone acetyltransferases. Anal. Biochem. 280, 308–314.
Kitz, R., and Wilson, I.B. (1962). Esters of methanesulfonic acid as irreversible
inhibitors of acetylcholinesterase. J. Biol. Chem. 237, 3245–3249.
Langner, M., Remy, P., and Bolm, C. (2005). Highly modular synthesis of
C1-symmetric aminosulfoximines and their use as ligands in copper-catalyzed
asymmetric Mukaiyama-Aldol reactions. Chem. Eur. J. 11, 6254–6265.
Choudhary, C., Kumar, C., Gnad, F., Nielsen, M.L., Rehman, M., Walther, T.C.,
Olsen, J.V., and Mann, M. (2009). Lysine acetylation targets protein complexes
and co-regulates major cellular functions. Science 325, 834–840.
Lau, O.D., Courtney, A.D., Vassilev, A., Marzilli, L.A., Cotter, R.J., Nakatani, Y.,
and Cole, P.A. (2000a). p300/CBP-associated factor histone acetyltransferase
processing of a peptide substrate. Kinetic analysis of the catalytic mechanism.
J. Biol. Chem. 275, 1953–1959.
Clayton, A.L., Rose, S., Barratt, M.J., and Mahadevan, L.C. (2000). Phosphoa-
cetylation of histone H3 on c-fos- and c-jun-associated nucleosomes upon
gene activation. EMBO J. 19, 3714–3726.
Cole, P.A. (2008). Chemical probes for histone-modifying enzymes. Nat.
Lau, O.D., Kundu, T.K., Soccio, R.E., Ait-Si-Ali, S., Khalil, E.M., Vassilev, A.,
Wolffe, A.P., Nakatani, Y., Roeder, R.G., and Cole, P.A. (2000b). HATs off:
selective synthetic inhibitors of the histone acetyltransferases p300 and
PCAF. Mol. Cell 5, 589–595.
Chem. Biol. 4, 590–597.
Copeland, R.A. (2000). Enzymes: A Practical Introduction to Structure, Mech-
anism, and Data Analysis, Second Edition (New York: Wiley-VCH).
Dekker, F.J., and Haisma, H.J. (2009). Histone acetyl transferases as emerging
Liu, X., Wang, L., Zhao, K., Thompson, P.R., Hwang, Y., Marmorstein, R., and
Cole, P.A. (2008a). The structural basis of protein acetylation by the p300/CBP
transcriptional coactivator. Nature 451, 846–850.
drug targets. Drug Discov. Today 14, 942–948.
Delaglio, F., Grzesiek, S., Vuister, G.W., Zhu, G., Pfeifer, J., and Bax, A. (1995).
NMRPipe: a multidimensional spectral processing system based on UNIX
pipes. J. Biomol. NMR 6, 277–293.
Liu, Y., Dentin, R., Chen, D., Hedrick, S., Ravnskjaer, K., Schenk, S., Milne, J.,
Meyers, D.J., Cole, P., Yates, J., 3rd, et al. (2008b). A fasting inducible switch
Chemistry & Biology 17, 471–482, May 28, 2010 ª2010 Elsevier Ltd All rights reserved 481