Novel 3,5-bis(bromohydroxybenzylidene)piperidin-4-ones as coactivator-associated arginine methyltransferase 1 inhibitors: enzyme selectivity and cellular activity.

Donghang Cheng (1) , Sergio Valente (2) , Sabrina Castellano (3) , Gianluca Sbardella (3) , Roberto Di Santo (2) , Roberta Costi (2) , Mark T Bedford (1) , Antonello Mai (2)

1 Anderson Cancer Center
2 Department of Medicinal Chemistry and Technologies
3 Dipartimento di Scienze Farmaceutiche e Biomediche

Coactivator-associated arginine methyltransferase 1 (CARM1) represents a valuable target for hormone-dependent tumors such as prostate and breast cancers. Here we report the enzyme and cellular characterization of the 1-benzyl-3,5-bis(3-bromo-4-hydroxybenzylidene)piperidin-4-one (7g) and its analogues 8a-l. Among them, 7g, 8e, and 8l displayed high and selective CARM1 inhibition, with lower or no activity against a panel of different PRMTs or HKMTs. In human LNCaP cells, 7g showed a significant dose-dependent reduction of the PSA promoter activity.

Domains: Pharmaceutical sciences

Donghang Cheng, Sergio Valente, Sabrina Castellano, Gianluca Sbardella, Roberto Di Santo, et al.. Novel 3,5-bis(bromohydroxybenzylidene)piperidin-4-ones as coactivator-associated arginine methyltransferase 1 inhibitors: enzyme selectivity and cellular activity.. Journal of Medicinal Chemistry, 2011, 54 (13), pp.4928-32. ⟨10.1021/jm200453n⟩. ⟨pasteur-00968654⟩