NAMPT: Metabolism, Cancer, and Drug Discovery

NAMPT & Metabolism

Metabolism IconThe unique metabolic requirements of rapidly reproducing cells are classical targets for cancer treatment.  For example, rapid growth creates a high demand for ATP used in the biosynthesis of DNA and proteins.  The enzymatic cofactors NAD+ and NADH contribute oxidizing and reducing agents required to generate ATP and regulate the resulting oxidative stress.  This need for high levels of ATP production makes the enzymatic pathways of sustaining NAD+ levels important to anti-cancer drug discovery.

Cells maintain adequate NAD+ levels through multiple enzymatic pathways.  Nicotinamide phosphoribosyl transferase 1 (NAMPT) is the rate limiting enzyme of the primary pathway for maintaining cellular NAD+.  The control function of this enzyme has made it an important target for drug discovery efforts designed to interfere with cancer metabolism 2.  

NAMPT & Cancer

Cancer IconA link between the enzymatic activity NAMPT and cancer metabolism is clearly established.  NAMPT is overexpressed relative to non-cancerous cells in lymphomas 3 astrocytomas 4 and carcinomas 5. Furthermore, inhibitors of NAMPT activities have shown anti-tumor properties in several models of organ-specific cancers 67.

The control of NAD+ metabolism by NAMPT connects this enzyme with several other well established, anti-cancer targets that depend on NAD+ consumption for enzymatic function.  PARPs are a family of 17 proteins that catalyze the NAD+ -dependent addition of poly(ADP-ribose) to proteins and are associated with response to DNA damage 8.  Sirtuins include seven NAD+ dependent deacetylases associated with post-translational modification of tumor suppressors and transcription factors 9.  Inhibition of NAMPT with small molecules contributes to both PARP 1011 and Sirtuin 1213 inhibition through NAD+ depletion.  This suggests synergy between inhibitors of NAMPT and these classes of enzymes could lead to the development of potent co-inhibitors.

PARP DNA Repair

 

Because of the promise of NAMPT as an anti-cancer target, it has been the subject of intensive efforts to find inhibitors as drug candidates.  Early inhibitors such as APO866/FK866 and GMX1778 have been extensively reported upon in the literature and studied in the clinic.  These compounds demonstrate low nM inhibition of NAMPT 14-16.  However, their toxicity profiles ultimately prevented them from reaching the therapeutic stage 2

Drug Discovery

Drug Discovery IconFurther advancements in the medicinal chemistry and dosing methods of NAMPT inhibitors continue to make this enzyme a highly relevant cancer target.  The compound LSN3154567 is a potential breakthrough developed by a combination of screening and rational design 17.  The result is an orally available compound that, when co-administered with the NAD+ precursor nicotinic acid, does not show the retinal and heamatological toxicities observed with older NAMPT inhibitors 17.

Another cleaver approach yielded the development of a dual NAMPT, Histone Deacetylase -1 (HDAC1) inhibitor 18.  Functional groups from known NAMPT and HDAC1 inhibitors where combined through a chemical linker (See figure below).  This molecule was then optimized through rounds of medicinal chemistry and inhibition assays.  The resulting molecule is a dual inhibitor with nM potencies against both enzymes. While still a proof of concept, this novel compound has the potential to capitalize on the synergistic inhibition of two well understood, anti-cancer targets.

NAMPT HDAC1 StructureReferences

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[17] Zhao, G., Green, C. F., Hui, Y. H., Prieto, L., Shepard, R., Dong, S., Wang, T., Tan, B., Gong, X., Kays, L., Johnson, R. L., Wu, W., Bhattachar, S., Del Prado, M., Gillig, J. R., Fernandez, M. C., Roth, K. D., Buchanan, S., Kuo, M. S., Geeganage, S., and Burkholder, T. P. (2017) Discovery of a Highly Selective NAMPT Inhibitor That Demonstrates Robust Efficacy and Improved Retinal Toxicity with Nicotinic Acid Co-administration, Mol Cancer Ther.
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