• A Correction to this article was published on 16 May 2018

This article has been updated

Abstract

The dynamic and reversible acetylation of proteins, catalysed by histone acetyltransferases (HATs) and histone deacetylases (HDACs), is a major epigenetic regulatory mechanism of gene transcription1 and is associated with multiple diseases. Histone deacetylase inhibitors are currently approved to treat certain cancers, but progress on the development of drug-like histone actyltransferase inhibitors has lagged behind2. The histone acetyltransferase paralogues p300 and CREB-binding protein (CBP) are key transcriptional co-activators that are essential for a multitude of cellular processes, and have also been implicated in human pathological conditions (including cancer3). Current inhibitors of the p300 and CBP histone acetyltransferase domains, including natural products4, bi-substrate analogues5 and the widely used small molecule C6466,7, lack potency or selectivity. Here, we describe A-485, a potent, selective and drug-like catalytic inhibitor of p300 and CBP. We present a high resolution (1.95 Å) co-crystal structure of a small molecule bound to the catalytic active site of p300 and demonstrate that A-485 competes with acetyl coenzyme A (acetyl-CoA). A-485 selectively inhibited proliferation in lineage-specific tumour types, including several haematological malignancies and androgen receptor-positive prostate cancer. A-485 inhibited the androgen receptor transcriptional program in both androgen-sensitive and castration-resistant prostate cancer and inhibited tumour growth in a castration-resistant xenograft model. These results demonstrate the feasibility of using small molecule inhibitors to selectively target the catalytic activity of histone acetyltransferases, which may provide effective treatments for transcriptional activator-driven malignancies and diseases.

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Change history

  • 16 May 2018

    In the originally published version of this Letter, authors Michael A. Patane, Arthur F. Kluge and Ce Wang were omitted from the author list; author 'Edward A. Kesicki' was misspelled; the Fig. 1a A-485 structure had an 'S' instead of a 'C' at the centre; Fig. 4d units were millimolar instead of micromolar; the headings were missing from the top of Extended Data Fig. 7e; and information specific to the authors M.A.P., A.F.K. and C.W. was missing from the 'Competing interests' statement. These errors have been corrected online.

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Acknowledgements

We thank V. Abraham and M. Smith for high content microscopy assistance; S. Ackler, D. He, Z. Yang and R. Bellin for assistance with cell proliferation assays; H. Liu for assistance with pharmacokinetic analyses; G. Diaz for help with compound selectivity screening; R. Henry for compound X-ray crystallography assistance; and E. Corey for the LuCap-77 CR patient derived xenograft model. Eurofins-Cerep supplied HAT selectivity, 7TM and ion channel off-target selectivity screening. Use of the IMCA-CAT beamline 17-ID at the Advanced Photon Source was supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with Hauptman-Woodward Medical Research Institute. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357. C.C. is supported by the Hallas Møller Investigator award from the Novo Nordisk Foundation (NNF14OC0008541). The Novo Nordisk Foundation Center for Protein Research is supported financially by the Novo Nordisk Foundation (Grant agreement NNF14CC0001). P.A.C. was supported by the NIH and FAMRI foundation. R.M. is supported by the NIH.

Author information

Author notes

    • Loren M. Lasko
    •  & Clarissa G. Jakob

    These authors contributed equally to this work.

Affiliations

  1. Discovery, Global Pharmaceutical Research and Development, AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064, USA

    • Loren M. Lasko
    • , Clarissa G. Jakob
    • , Rohinton P. Edalji
    • , Wei Qiu
    • , Debra Montgomery
    • , Enrico L. Digiammarino
    • , T. Matt Hansen
    • , Roberto M. Risi
    • , Robin Frey
    • , Vlasios Manaves
    • , Bailin Shaw
    • , Mikkel Algire
    • , Paul Hessler
    • , Lloyd T. Lam
    • , Tamar Uziel
    • , Emily Faivre
    • , Debra Ferguson
    • , Fritz G. Buchanan
    • , Ruth L. Martin
    • , Maricel Torrent
    • , Gary G. Chiang
    • , Chaohong Sun
    • , Saul H. Rosenberg
    • , Michael R. Michaelides
    • , Albert Lai
    •  & Kenneth D. Bromberg
  2. eFFECTOR Therapeutics, 11180 Roselle St, Suite A, San Diego, California 92121, USA

    • Gary G. Chiang
  3. Petra Pharma Corporation, 430 E. 29th St, Suite 435, New York, New York 10016, USA

    • Kannan Karukurichi
    •  & Ed Kesicki
  4. Faraday Pharmaceuticals, 1616 Eastlake Ave E., Suite 560, Seattle, Washington 98102, USA

    • J. William Langston
  5. Department of Proteomics, the Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark

    • Brian T. Weinert
    •  & Chunaram Choudhary
  6. Cascadian Therapeutics, Inc., 2601 Fourth Avenue, Suite 500, Seattle, Washington 98121, USA

    • Peter de Vries
  7. Van Drie Research, 109 Millpond, Andover, Massachusetts 01845, USA

    • John H. Van Drie
  8. Accelerator Corporation, 430 East 29th St, New York, New York 10106, USA

    • David McElligott
  9. Perelman School of Medicine, University of Pennsylvania, 421 Curie Blvd, Philadelphia, Pennsylvania 19104, USA

    • Ronen Marmorstein
  10. Johns Hopkins University, 725 N. Wolfe St, Baltimore, Maryland 21205, USA

    • Philip A. Cole
  11. I-to-D, Inc., PO Box 6177, Lincoln, Massachusetts 01773, USA

    • Arthur F. Kluge
  12. Mitobridge, Inc., 1030 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA

    • Michael A. Patane
  13. China Novartis In stitutes for BioMedical Research, No. 4218 Jinke Road, Zhangjiang Hi-Tech Park, Pudong District, Shanghai 201203, China

    • Ce Wang

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Contributions

J.H.V.D. developed and conducted the virtual ligand screen, and K.K. screened its hits and analysed the results. T.M.H., R.M.R., R.F. and M.R.M. designed compounds. M.T. generated 3D protein homology models and small molecule docking/computational models. R.P.E produced protein, W.Q. produced protein crystals, and C.G.J. performed X-ray structure determination and analysis. E.L.D. performed surface plasmon resonance experiments and analysis. K.K., V.M. and M.A. performed in vitro biochemical studies. K.D.B. and L.M.L. performed cellular acetyl and methyl mark high content microscopy assays. B.S., D.Mo., J.W.L, L.M.L., L.T.L. and K.D.B. performed cellular sensitivity, qPCR and western blotting experiments and analysis. B.T.W. and C.C. performed auto-acetylation mass spectrometry experiments. P.H., L.T.L. and T.U. performed microarray experiments and analysis. E.F. performed ChIP experiments and analysis. D.F. and F.G.B. performed in vivo xenograft experiments. D.Mc., J.W.L., P.d.V., E.K., R.L.M., R.M., P.A.C., G.G.C, C.S., M.R.M, S.H.R., A.L. and K.D.B designed studies and interpreted results. K.D.B. and M.R.M. wrote the paper.

Competing interests

This study was sponsored by AbbVie. AbbVie contributed to the study design, research and interpretation of data, and to writing, reviewing and approving the publication. L.M.L, C.G.J., R.P.E, W.Q., D.Mo., E.L.D., T.M.H, R.M.R, R.F., V.M., B.S., M.A., P.H., L.T.L., T.U., E.F., D.F., F.G.B., M.T., G.G.C., C.S., M.R.M., S.H.R., A.L. and K.D.B. were employees of AbbVie at the time of the study. K.K., J.W.L., P.d.V., D.Mc., and E.K. were employees of Acylin which provided assets to AbbVie at the time of the study. AbbVie licensed and provided funding for these assets. R.M. and P.A.C. are co-founders of Acylin and consultants for AbbVie. A.F.K. and M.A.P. were consultants to Acylin at the time of the study. C.W. was an employee of BioDuro, which was contracted by Acylin at the time of the study.

Corresponding authors

Correspondence to Albert Lai or Kenneth D. Bromberg.

Reviewer Information Nature thanks J. Jin and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplemental information

    This file contains supplemental text, tool compound synthesis, on-line methods and supplemental references.

  2. 2.

    Supplementary Figure 1

    Uncropped western blots for Extended Data Figures 5, 6, 7, and 10

  3. 3.

    Reporting Summary

Word documents

  1. 1.

    Supplementary Table 1

    Summary of screening data of hits from VLS (Virtual Ligand Screen)

Excel files

  1. 1.

    Supplementary Table 2

    Comparison of IC50 values for inhibition of p300 acetyltransferase activity by A-485 and literature reported p300/CBP tool compounds

  2. 2.

    Supplementary Table 3

    Percent inhibition of activity of the indicated HATs by A-485

  3. 3.

    Supplementary Table 4

    IC50 values of binding of the indicated bromodomains by A-485

  4. 4.

    Supplementary Table 5

    Percent binding of the indicated non-epigenetic proteins by A-485 and A-486

  5. 5.

    Supplementary Table 6

    Percent inhibition of activity of the indicated non-epigenetic proteins by A-485 and A-486

  6. 6.

    Supplementary Table 7

    IC50 values of binding of the indicated kinases by A-485

  7. 7.

    Supplementary Table 8

    EC50 values for inhibition of histone acetyl marks upon treatment with the indicated compounds

  8. 8.

    Supplementary Table 9

    Acetylation sites on the CBP/p300 auto-acetylation loop (ref 13), and their regulation by A-485 in HeLa cells

  9. 9.

    Supplementary Table 10

    EC50 values for inhibition of proliferation of cancer cell lines by A-485

  10. 10.

    Supplementary Table 11

    Number of significant gene expression changesa induced by A-485 treatment for 6 hours in prostate cancer cells

  11. 11.

    Supplementary Table 12

    PK profile of A-485 after a single intraperitoneal dose

  12. 12.

    Supplementary Table 13

    Plasma and brain exposures 24 h post a single oral dose of A-485

  13. 13.

    Supplementary Table 14

    Antibodies used in this study

  14. 14.

    Supplementary Table 15

    IDT PrimeTime qPCR assay primer and probe sequences used in this study for qPCR assays

  15. 15.

    Supplementary Table 16

    Primer sequences used in this study for ChIP qPCR assays

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DOI

https://doi.org/10.1038/nature24028

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