NAMPT is currently of great interest in a number of fields of research, including NAD biology, metabolism and inflammation. By regulating NAD availability, NAMPT is able to control both cell viability and the inflammatory response. NAMPT may thus represent a novel target for drug discovery in various therapeutic areas, including oncology and inflammation. Additionally, work at Babraham has shown that the NAMPT inhibitor FK866 protects axons suggesting that targeting NAMPT has potential in treating axon degeneration. This observation prompted the instigation of a collaboration with Charles River seeking novel NAMPT inhibitors.<br/><br/>A publicly available X-ray crystal structure of NAMPT in complex with FK-866 together with the structures of the NAMPT inhibitors FK-866 and MPI-0479626 were used as the basis for a structure- and ligand-based virtual screening campaign. This resulted in the ordering of 102 compounds from commercial vendors. Of the 99 compounds received, 42 showed 50% inhibition or greater when screened at 100μM in singlet. 40 compounds were confirmed to be hits when retested in duplicate at 100μM and IC50 values were determined for these. Five compounds had sub-micromolar activity in the assay, with the most active showing IC50 values of 220nM and 320nM, respectively<br/>.<br/>A follow-up round of virtual screening was carried out leading to the purchase and testing of an additional 79 compounds. From this set of compounds, two novel and potent series of NAMPT inhibitors were identified, one of which showed a statistically significant protective effect when tested in a cellular model of axon degeneration.

Application of virtual screening to the discovery of novel, nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with potential for the treatment of axonopathies

251st National Meeting (2016)

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