4N9D: Fragment-based Design of 3-aminopyridine-derived Amides as Potent Inhibitors of Human Nicotinamide Phosphoribosyltransferase (Nampt)

Citation:
Abstract
The fragment-based identification of two novel and potent biochemical inhibitors of the nicotinamide phosphoribosyltransferase (NAMPT) enzyme is described. These compounds (51 and 63) incorporate an amide moiety derived from 3-aminopyridine, and are thus structurally distinct from other known anti-NAMPT agents. Each exhibits potent inhibition of NAMPT biochemical activity (IC50=19 and 15nM, respectively) as well as robust antiproliferative properties in A2780 cell culture experiments (IC50=121 and 99nM, respectively). However, additional biological studies indicate that only inhibitor 51 exerts its A2780 cell culture effects via a NAMPT-mediated mechanism. The crystal structures of both 51 and 63 in complex with NAMPT are also independently described.
PDB ID: 4N9DDownload
MMDB ID: 117688
PDB Deposition Date: 2013/10/20
Updated in MMDB: 2014/02
Experimental Method:
x-ray diffraction
Resolution: 1.7  Å
Source Organism:
Similar Structures:
Biological Unit: dimeric; determined by author, and by software (PISA)
Molecular Components
Label Count Molecule
Proteins (2 molecules)
2
Nicotinamide Phosphoribosyltransferase
Molecule annotation
Chemicals (10 molecules)
1
2
2
2
3
6
* Click molecule labels to explore molecular sequence information.

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