Sunitinib-based Proteolysis Targeting Chimeras (PROTACs) reduced the protein levels of FLT-3 and c-KIT in leukemia cell lines

  • Bioorg Med Chem Lett. 2022 Dec 15:78:129041. doi: 10.1016/j.bmcl.2022.129041.
Jiadai Zhai  1 ,  Chuang Li  2 ,  Bingxia Sun  2 ,  Sinan Wang  2 ,  Yuting Cui  2 ,  Qingzhi Gao  3 ,  Feng Sang  4
Affiliations
  • 1. School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, PR China.
  • 2. School of Life Sciences and Medicine, Shandong University of Technology, Zibo 255049, PR China.
  • 3. School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, PR China. Electronic address: [email protected].
  • 4. School of Life Sciences and Medicine, Shandong University of Technology, Zibo 255049, PR China. Electronic address: [email protected].
PMID: 36332882 DOI: 10.1016/j.bmcl.2022.129041
Abstract

Proteolysis Targeting Chimeras (PROTACs) based on multi-target inhibitors have been reported several times recently. The advantages of PROTACs technology and the synergistic mechanism of multi-target drugs endow this class of protein degraders with special research significance. Herein, twelve new PROTACs based on Sunitinib and VHL-ligand were synthesized and evaluated for their in vitro Anticancer activities. Among them, PROTACs 5 (IC50 = 2.9 ± 1.5 μM) exhibited the most significant antiproliferative activity against HL-60 cells. Western blot results showed that PROTAC 5 reduced the protein levels of Flt-3 and c-Kit in HL-60 cells, and induced the degradation of Flt-3 via the ubiquitin-proteasome system. Moreover, PROTACs 5 and 6 reduced the protein levels of Flt-3 in K562 cells. These results suggest that PROTAC 5 has the potential for further research, especially in combination with small molecule kinase inhibitors to study multidrug resistance of tyrosine kinase inhibitors in Cancer treatment.

Keywords
Anticancer; Proteolysis targeting chimeras; Sunitinib; Synthesis; von Hippel-Lindau.
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