Identification Of Unprecedented Atp-Competitive Choline Kinase Inhibitors

In this article we describe the identification of unprecedented ATP-competitive ChoK alpha inhibitors starting from initial hit NMS-P830 that binds to ChoK alpha in an ATP concentration-dependent manner. This result is confirmed by the co-crystal structure of NMS-P830 in complex with Delta 75-ChoK alpha. NMS-P830 is able to inhibit ChoK alpha in cells resulting in the reduction of intracellular phosphocholine formation. A structure-based medicinal chemistry program resulted in the identification of selective compounds that have good biochemical activity, solubility and metabolic stability and are suitable for further optimization. The ChoK alpha inhibitors disclosed in this article demonstrate for the first time the possibility to inhibit ChoK alpha with ATP-competitive compounds.