We have recently published the results of studies seeking new small molecule inhibitors of the cell division cycle 25B dual specificity phosphatase (Cdc25B), which regulates the normal progression of the mammalian cell cycle by dephosphorylating and activating cyclin-dependent kinase complexes, particularly in response to DNA damage. Elevated Cdc25B levels enable a bypass of normal cell cycle checkpoints, and the overexpression of Cdc25B has been linked to a variety of human cancers. In this manuscript, we describe the synthesis and biological evaluation of a series of non-quinoid inhibitors of Cdc25B containing the 3-aminoisoquinolin-1(2H)-one pharmacophore. A new lead structure, 6-(3-aminophenyl)-3-(phenylamino)isoquinolin-1(2H)-one (13), is a reversible, competitive Cdc25B inhibitor with a Ki of 1.9 μM. It prevented human cancer cell growth and blocked Cdc25B-mediated mitotic checkpoint bypass. Molecular docking studies support binding near the catalytic site. You can read more about this compound in Bioorganic and Medicinal Chemistry (volume 23 pages 2810-2816, 2015) (doi:10.1016/j.bmc.2015.01.043). The authors are Kara George Rosenker, William Paquette, Paul A. Johnston, Elizabeth R. Sharlow, Andreas Vogt, Ahmet Bakan, John S. Lazo and Peter Wipf.
Tags: cancer, Cdc25B, small molecule