FK866

FK866, also known as APO866, is a small-molecule inhibitor of nicotinamide phosphoribosyltransferase (NAMPT), an enzyme that governs the rate-limiting step of the NAD+ salvage pathway. NAMPT converts nicotinamide to nicotinamide mononucleotide, a precursor of NAD+. By inhibiting NAMPT, FK866 reduces intracellular NAD+ levels, which disrupts cellular energy metabolism and can trigger apoptosis in susceptible cells, particularly cancer cells with high metabolic demands.

Mechanistically, FK866 binds to NAMPT and acts as a potent, selective inhibitor. The resulting NAD+ depletion impairs energy production and other NAD+-dependent processes, leading to cell stress and death in many tumor models. The cytotoxic effect is often more pronounced in malignant cells than in normal cells, though NAD+ depletion can also affect normal tissues at higher doses.

The anti-tumor activity observed with FK866 has driven its investigation in preclinical studies and early-phase clinical trials under the name APO866. Trials have explored various hematologic and solid tumors, but as a non- approved therapy, results have been mixed and dose-limiting toxicities have tempered enthusiasm. Research has continued into NAMPT inhibitors as a class, with interest in combination strategies that may enhance efficacy or mitigate resistance, including pairing with chemotherapy, radiotherapy, or other targeted agents.

In summary, FK866 is a NAMPT inhibitor that reduces NAD+ biosynthesis to exert anti-cancer effects in preclinical and early clinical settings, reflecting ongoing interest in exploiting NAD+ metabolism for cancer therapy.

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