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.

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