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

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.

Automated summary

p300 and CBP play essential roles in cellular processes and dysregulation of their histone acetyltransferase activity is linked to various human diseases. The novel drug-like compound 21 is a selective orally bioavailable inhibitor of p300/CBP histone acetyltransferase, more potent than A-485 and lacking off-target inhibition of dopamine and serotonin transporters.