Ispinesib as an Effective Warhead for the Design of Autophagosome-Tethering Chimeras: Discovery of Potent Degraders of Nicotinamide Phosphoribosyltransferase (NAMPT)

  • J Med Chem. 2022 Jun 9;65(11):7619-7628. doi: 10.1021/acs.jmedchem.1c02001.
Guoqiang Dong  1 ,  Ying Wu  1  2 ,  Junfei Cheng  1 ,  Long Chen  1 ,  Rui Liu  3 ,  Yu Ding  3 ,  Shanchao Wu  1 ,  Junhui Ma  1 ,  Chunquan Sheng  1
Affiliations
  • 1. School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
  • 2. Department of Pharmacy, 920th Hospital of Joint Logistics Support Force, Kunming 650032, China.
  • 3. School of Life Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China.
PMID: 35588495 DOI: 10.1021/acs.jmedchem.1c02001
Abstract

Autophagosome-tethering compounds (ATTECs) are an emerging new technology in targeted protein degradation. However, effective tools and successful examples for autophagosome-tethering chimeras are still rather limited. Herein, ATTEC ispinesib was identified for the first time to be an effective warhead to design autophagosome-tethering chimeras. As a conceptual validation study, the first generation of autophagic degraders of nicotinamide phosphoribosyltransferase (NAMPT) were developed by connecting the NAMPT Inhibitor and LC3-binding ispinesib through a flexible linker. In particular, compound A3 significantly induced the degradation of NAMPT through the autophagy-lysosomal pathway, leading to excellent cellular antitumor potency. Ispinesib may have broad applications in the design of potent autophagosome-tethering chimeras.

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