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

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.

SUBMITTER: Ji Z

PROVIDER: S-EPMC8392731 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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

Ji Zhiqin Z Clark Richard F RF Bhat Vikram V Matthew Hansen T T Lasko Loren M LM Bromberg Kenneth D KD Manaves Vlasios V Algire Mikkel M Martin Ruth R Qiu Wei W Torrent Maricel M Jakob Clarissa G CG Liu Hong H Cole Philip A PA Marmorstein Ronen R Kesicki Edward A EA Lai Albert A Michaelides Michael R MR

Bioorganic & medicinal chemistry letters 20210223

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 ...[more]

PMID: 33631370

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