Novel PROTAC to Degrade NAMPT Enzyme

NAD+ is a coenzyme that transmits hydrogen ions and is involved in various physiological functions such as energy synthesis and DNA repair. It also acts as a cellular secretory protein that promotes tumorigenesis and malignant progression. Previous strategies to target NAMPT have focused on the development of conventional enzyme activity inhibitors, but have been clinically ineffective. Protein-targeted degradation, on the other hand, has a very promising developmental potential due to its ability to both prevent NAMPT from performing its enzymatic catalytic function and inhibit its function as an extracellular secretory protein.

Fan Gaofeng's group at Shanghai University of Science and Technology's College of Life Sciences and Technology, Jiang Biao's group at the Institute of Immunochemistry, and Gluetacs Therapeutics recently published an article in Cell Chemical Biology, a Cell series journal, titled Addressing Enzymatic-Independent Tumor-Promoting Function of NAMPT via PROTAC-Mediated Degradation, reporting two NAMPT PROTAC compounds that precisely eliminate both internal and extracellular forms of NAMPT in a wide spectrum of tumor cell lines, altering tumor cells' metabolic fitness and better killing tumor cells.

The researchers chose FK866, the first NAMPT inhibitor reported, as the NAMPT target protein ligand. The eutectic structure of FK866 and NAMPT protein revealed that the terminal benzene ring was in the solvent-exposed area, and varied length linkers were connected to the CRBN E3 ligase ligand via piperazine as the elicitation site. PROTAC compounds 630120 and 630121 were shown to be highly selective for NAMPT degradation.

Both PROTAC compounds enable efficient degradation of NAMPT protein in hematoma cell lines and can affect the secretion process by degrading iNAMPT, which ultimately leads to a decrease in eNAMPT levels. Exocytosed eNAMPT has growth factor-like effects and can activate downstream NF-κB and MAPK-ERK signaling pathways. Therefore, the PROTAC-mediated decrease in exocytosed eNAMPT levels can effectively inhibit NF-κB as well as ERK signaling pathway activation in tumor cells, exhibiting superior killing effects over inhibitors in acute leukemia cells.

The PROTAC protein degradation technology was used in this study to design and synthesize degradation agents targeting NAMPT from scratch, and the candidate compounds with good activity after the initial screening were subjected to in-depth biological evaluation and mechanistic investigation to find compounds with dual inhibition of enzymatic activity and secretory protein function, which can play a role not easily achieved by traditional inhibitors and compensate for the shortcomings of traditional inhibitors. This work provides a solid experimental foundation for the development of PROTAC drugs targeting NAMPT, as well as critical theoretical support for validating the scientific importance of NAMPT protein degradation for the treatment of various kinds of cancers.

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