molecules of the month


femtomolar EZH2 hist. methyltransferase inh.

oral activity (10-25 mg/kg QD) in xenograft

from opt. of prior ligand

J. Bio. Chem., Jan. 30, 2021

Constellation Pharma, Cambridge, MA

1 min read

12. The 2nd generation Constellation EZH2 histone methyltransferase inhibitor, CPI-1328, is an extremely potent tool compound with reversible femtomolar activity against EZH2, and is one of the most potent reversible small inhibitors ever reported. Previous analyses have suggested an empirical barrier for non-covalent inhibitors around 10 pM. The molecule builds on a finding from their previous paper that a thiomethyl group is critical for increased drug residence time. This activity translated to in vivo activity at 25 mg/kg QD despite the comprehensive target coverage thought to be needed against EZH2 to elicit an effect.

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