2. Academic Validation
  3. Addressing the Enzyme-independent tumor-promoting function of NAMPT via PROTAC-mediated degradation

Addressing the Enzyme-independent tumor-promoting function of NAMPT via PROTAC-mediated degradation

  • Cell Chem Biol. 2022 Nov 17;29(11):1616-1629.e12. doi: 10.1016/j.chembiol.2022.10.007.
Xiaotong Zhu 1,  Haixia Liu 2,  Li Chen 1,  Chenxu Wu 1,  Xuesong Liu 1,  Yong Cang 1,  Biao Jiang 3,  Xiaobao Yang 4,  Gaofeng Fan 5
Affiliations

Affiliations

  • 1 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 2 School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210, China; Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China; University of the Chinese Academy of Sciences, Beijing 100049, China.
  • 3 CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China. Electronic address: jiangbiao@shanghaitech.edu.cn.
  • 4 Gluetacs Therapeutics (Shanghai) Co., Ltd., Zhangjiang Hi-Tech Park, Shanghai 201210, China. Electronic address: yang.xiaobao@gluetacs.com.
  • 5 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: fangf@shanghaitech.edu.cn.
PMID: 36323324 DOI: 10.1016/j.chembiol.2022.10.007
Abstract

Aberrant overexpression of nicotinamide phosphoribosyltransferase (NAMPT) has been reported in a variety of tumor cells and is a poor prognosis factor for patient survival. It plays an important role in tumor cell proliferation, acting concurrently as an nicotinamide adenine dinucleotide (NAD+) synthase and, unexpectedly, as an extracellular signaling molecule for several tumor-promoting pathways. Although previous efforts to modulate NAMPT activity were limited to enzymatic inhibitors with low success in clinical studies, protein degradation offers the possibility to simultaneously disrupt NAMPT's Enzyme activity and ligand capabilities. Here we report the development of two highly selective proteolysis-targeting chimeras (PROTACs) that promote NAMPT degradation in a cereblon-dependent manner. Both PROTAC degraders outperform a clinical candidate, FK866, in killing effect on hematological tumor cells. These results emphasize the importance and feasibility of applying PROTACs as a superior strategy for targeting proteins with multiple tumor-promoting functions like NAMPT, which is not easily achieved by conventional enzymatic inhibitors.

Keywords

NAD(+); PROTAC; eNAMPT; enzyme-independent; iNAMPT.

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