Display options
Cite
Michaelides MR, Kluge A, Patane M, et al. Discovery of Spiro Oxazolidinediones as Selective, Orally Bioavailable Inhibitors of p300/CBP Histone Acetyltransferases. ACS Med Chem Lett. 2017;9(1):28-33doi: 10.1021/acsmedchemlett.7b00395.
Michaelides, M. R., Kluge, A., Patane, M., Van Drie, J. H., Wang, C., Hansen, T. M., Risi, R. M., Mantei, R., Hertel, C., Karukurichi, K., Nesterov, A., McElligott, D., de Vries, P., Langston, J. W., Cole, P. A., Marmorstein, R., Liu, H., Lasko, L., Bromberg, K. D., Lai, A., & Kesicki, E. A. (2018). Discovery of Spiro Oxazolidinediones as Selective, Orally Bioavailable Inhibitors of p300/CBP Histone Acetyltransferases. ACS medicinal chemistry letters, 9(1), 28-33. https://doi.org/10.1021/acsmedchemlett.7b00395
Michaelides, Michael R, et al. "Discovery of Spiro Oxazolidinediones as Selective, Orally Bioavailable Inhibitors of p300/CBP Histone Acetyltransferases." ACS medicinal chemistry letters vol. 9,1 (2018): 28-33. doi: https://doi.org/10.1021/acsmedchemlett.7b00395
Michaelides MR, Kluge A, Patane M, Van Drie JH, Wang C, Hansen TM, Risi RM, Mantei R, Hertel C, Karukurichi K, Nesterov A, McElligott D, de Vries P, Langston JW, Cole PA, Marmorstein R, Liu H, Lasko L, Bromberg KD, Lai A, Kesicki EA. Discovery of Spiro Oxazolidinediones as Selective, Orally Bioavailable Inhibitors of p300/CBP Histone Acetyltransferases. ACS Med Chem Lett. 2017 Dec 13;9(1):28-33. doi: 10.1021/acsmedchemlett.7b00395. eCollection 2018 Jan 11. PMID: 29348807; PMCID: PMC5767893.
Copy Download .nbib Format: NLM
Share it on

ACS Med Chem Lett. 2017 Dec 13;9(1):28-33. doi: 10.1021/acsmedchemlett.7b00395. eCollection 2018 Jan 11.

Discovery of Spiro Oxazolidinediones as Selective, Orally Bioavailable Inhibitors of p300/CBP Histone Acetyltransferases.

ACS medicinal chemistry letters

Michael R Michaelides, Arthur Kluge, Michael Patane, John H Van Drie, Ce Wang, T Matthew Hansen, Roberto M Risi, Robert Mantei, Carmen Hertel, Kannan Karukurichi, Alexandre Nesterov, David McElligott, Peter de Vries, J William Langston, Philip A Cole, Ronen Marmorstein, Hong Liu, Loren Lasko, Kenneth D Bromberg, Albert Lai, Edward A Kesicki

Affiliations

  1. AbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
  2. Acylin Therapeutics, Inc., 1616 Eastlake Avenue E, Suite 200, Seattle, Washington 98012, United States.
  3. BioDuro, No. 29 Life Science Park Road, Changping District, Beijing 102206, P. R. China.

PMID: 29348807 PMCID: PMC5767893 DOI: 10.1021/acsmedchemlett.7b00395

Abstract

p300 and its paralog CBP can acetylate histones and other proteins and have been implicated in a number of diseases characterized by aberrant gene activation, such as cancer. A novel, highly selective, orally bioavailable histone acetyltransferase (HAT) domain inhibitor has been identified through virtual ligand screening and subsequent optimization of a unique hydantoin screening hit. Conformational restraint in the form of a spirocyclization followed by substitution with a urea led to a significant improvement in potency. Replacement of the hydantoin moiety with an oxazolidinedione followed by fluoro substitution led to

Conflict of interest statement

The authors declare the following competing financial interest(s): This study was sponsored by AbbVie. AbbVie contributed to the study design, research, and interpretation of data, writing, reviewing,

References

  1. Oncogene. 2015 Sep 17;34(38):4901-13 - PubMed
  2. Proteins. 1995 Dec;23(4):557-60 - PubMed
  3. Cancer Res. 2015 Dec 1;75(23 ):5106-5119 - PubMed
  4. Cell. 1999 Apr 30;97(3):361-9 - PubMed
  5. Biochem Pharmacol. 2016 Feb 15;102:130-140 - PubMed
  6. Proc Natl Acad Sci U S A. 2014 May 27;111(21):7531-6 - PubMed
  7. Curr Pharm Des. 2013;19(28):5051-64 - PubMed
  8. ACS Med Chem Lett. 2015 Oct 31;7(2):151-5 - PubMed
  9. Nat Rev Mol Cell Biol. 2014 Nov;15(11):703-8 - PubMed
  10. Chem Biol. 2010 May 28;17(5):471-82 - PubMed
  11. Cold Spring Harb Perspect Med. 2017 Mar 1;7(3):null - PubMed
  12. Cancer Cell. 2017 Jul 10;32(1):9-25 - PubMed
  13. EMBO J. 2011 Jan 19;30(2):249-62 - PubMed
  14. Oncogene. 2014 Apr 24;33(17 ):2169-78 - PubMed
  15. Chem Rev. 2015 Mar 25;115(6):2419-52 - PubMed
  16. J Med Chem. 2016 Feb 25;59(4):1249-70 - PubMed
  17. Curr Med Chem. 2017 Feb 23;:null - PubMed
  18. Annu Rev Biophys Biophys Chem. 1986;15:97-117 - PubMed
  19. Nat Rev Genet. 2009 Jan;10(1):32-42 - PubMed
  20. Elife. 2016 Jan 05;5:null - PubMed
  21. Nature. 2017 Oct 5;550(7674):128-132 - PubMed
  22. Biopolymers. 2013 Feb;99(2):98-111 - PubMed
  23. J Pharm Sci. 2010 Aug;99(8):3620-7 - PubMed
  24. ACS Med Chem Lett. 2016 Mar 15;7(5):531-6 - PubMed
  25. J Med Chem. 2014 Oct 23;57(20):8238-48 - PubMed
  26. Nature. 2008 Feb 14;451(7180):846-50 - PubMed
  27. J Am Chem Soc. 2014 Jul 2;136(26):9308-19 - PubMed
  28. Curr Opin Struct Biol. 2008 Dec;18(6):741-7 - PubMed

Publication Types

Grant support