2. Academic Validation
  3. Discovery of potent NAMPT-Targeting PROTACs using FK866 as the warhead

Discovery of potent NAMPT-Targeting PROTACs using FK866 as the warhead

  • Bioorg Med Chem Lett. 2023 Aug 15;92:129393. doi: 10.1016/j.bmcl.2023.129393.
Peifeng Zhang 1,  Wei Wang 2,  Menglu Guo 2,  Luozhu Zhou 2,  Guoqiang Dong 2,  Defeng Xu 3,  Chunquan Sheng 4
Affiliations

Affiliations

  • 1 School of Pharmacy, Changzhou University, Changzhou 213164, China.
  • 2 School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
  • 3 School of Pharmacy, Changzhou University, Changzhou 213164, China. Electronic address: markxu@cczu.edu.cn.
  • 4 School of Pharmacy, Second Military Medical University, Shanghai 200433, China. Electronic address: shengcq@smmu.edu.cn.
PMID: 37369332 DOI: 10.1016/j.bmcl.2023.129393
Abstract

Nicotinamide phosphoribosyltransferase (NAMPT) has emerged as a promising target for Cancer therapy due to its strong correlation with nicotinamide adenine dinucleotide (NAD+) metabolism and tumorigenesis. Proteolysis targeting chimeras (PROTACs) provided an attractive strategy for developing NAMPT-targeting NAD+-depleting Cancer drugs. Herein, a series of von Hippel-Lindau (VHL)-recruiting NAMPT-targeting PROTACs were designed using NAMPT Inhibitor FK866 as the warhead. Among them, compound C5 degraded NAMPT (DC50 = 31.7 nM) in a VHL- and proteasome-dependent manner. Moreover, compound C5 effectively inhibited the proliferation of A2780 cells (IC50 = 30.6 nM) and significantly reduced the general cytotoxicity of FK866 to normal cells.

Keywords

Degradation potency; Drug discovery; FK866; NAMPT; PROTAC.

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