Inhibition of NAMPT by PAK4 Inhibitor

The serine/threonine kinase PAK4 plays a key role in regulating cell proliferation, survival, migration, and invasion. Its overexpression is associated with poor prognosis in certain cancers. KPT-9274, initially identified as a PAK4 inhibitor, has been shown to significantly suppress the growth of triple-negative breast cancer cells and mammary tumors in mouse models, as well as inhibit other types of cancer cells. Interestingly, KPT-9274 also targets NAMPT (nicotinamide phosphoribosyltransferase), an enzyme essential for NAD (nicotinamide adenine dinucleotide) synthesis, which is critical for cellular energy production and growth.

This dual activity raised the question of whether the observed growth KPT 9274 inhibition was due to PAK4 inhibition, NAMPT inhibition, or a combination of both. To investigate further, we tested other PAK4 inhibitors that also suppress cell growth, aiming to determine whether they similarly inhibit NAMPT. Our experiments, conducted using both cell-free assays and a breast cancer cell line, confirmed that multiple PAK4 inhibitors also block NAMPT activity. Molecular docking studies provided additional insights into the mechanism of action, revealing specific interactions between residues on the inhibitors and both NAMPT and PAK4.

These findings suggest that the mechanism by which PAK4 inhibitors affect cancer cell growth may be more complex than previously understood. Further research is needed to clarify their dual effects and better understand their therapeutic potential.