Discovery of spirohydantoins as selective, orally bioavailable inhibitors of p300/CBP histone acetyltransferases

  • Bioorg Med Chem Lett. 2021 May 1:39:127854. doi: 10.1016/j.bmcl.2021.127854.
Zhiqin Ji  1 ,  Richard F Clark  2 ,  Vikram Bhat  2 ,  T Matthew Hansen  2 ,  Loren M Lasko  2 ,  Kenneth D Bromberg  2 ,  Vlasios Manaves  2 ,  Mikkel Algire  2 ,  Ruth Martin  2 ,  Wei Qiu  2 ,  Maricel Torrent  2 ,  Clarissa G Jakob  2 ,  Hong Liu  3 ,  Philip A Cole  4 ,  Ronen Marmorstein  5 ,  Edward A Kesicki  6 ,  Albert Lai  2 ,  Michael R Michaelides  2
Affiliations
  • 1. Abbvie, Inc. 1 North Waukegan Road, North Chicago, IL-60064, United States. Electronic address: [email protected].
  • 2. Abbvie, Inc. 1 North Waukegan Road, North Chicago, IL-60064, United States.
  • 3. Novartis Institutes for BioMedical Research, 220 Massachusetts Avenue Cambridge, MA 02139, United States.
  • 4. Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, United States.
  • 5. Perelman School of Medicine, University of Pennsylvania BRB II/III, Room 454, 421 Curie Blvd, Philadelphia, PA 19104, United States.
  • 6. Loxo Oncology at Lilly, 450 E 29(th) St, Suite 506, New York, NY, 10016, United States.
PMID: 33631370 DOI: 10.1016/j.bmcl.2021.127854
Abstract

p300 and CREB-binding protein (CBP) are essential for a multitude of cellular processes. Dysregulation of p300/CBP Histone Acetyltransferase activity is linked to a broad spectrum of human diseases including cancers. A novel drug-like spirohydantoin (21) has been discovered as a selective orally bioavailable inhibitor of p300/CBP Histone Acetyltransferase. Lead compound 21 is more potent than the first-in-class lead A-485 in both enzymatic and cellular assays and lacks the off-target inhibition of dopamine and serotonin transporters, that was observed with A-485.

Keywords
CBP; Histone acetyltransferase; P300; Spirohydantoin.