Fragment-based discovery of a potent NAMPT inhibitor

Bioorganic & Medicinal Chemistry Letters
Alla KorepanovaAndrew M Petros

Abstract

NAMPT expression is elevated in many cancers, making this protein a potential target for anticancer therapy. We have carried out both NMR based and TR-FRET based fragment screens against human NAMPT and identified six novel binders with a range of potencies. Co-crystal structures were obtained for two of the fragments bound to NAMPT while for the other four fragments force-field driven docking was employed to generate a bound pose. Based on structural insights arising from comparison of the bound fragment poses to that of bound FK866 we were able to synthetically elaborate one of the fragments into a potent NAMPT inhibitor.

References

Apr 6, 2005·Drug Discovery Today·Cele Abad-Zapatero, James T Metz
Jun 20, 2006·Nature Structural & Molecular Biology·Javed A KhanLiang Tong
Jan 7, 2014·Current Protocols in Chemical Biology·Darren W BegleyEdward R Zartler
Jan 18, 2014·Bioorganic & Medicinal Chemistry Letters·Peter S DragovichXiaozhang Zheng

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Citations

Jun 2, 2020·Frontiers in Pharmacology·Ubaldina GalliAmbra A Grolla
Jan 9, 2020·Journal of Medicinal Chemistry·Daniel A ErlansonPaul N Mortenson

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