Discovery of degrader for FLT3, GSPT1 and IKZF1/3 proteins merging PROTAC and molecular glue targeting FLT3-ITD mutant acute myeloid leukemia

  • Eur J Med Chem. 2025 Oct 15:296:117893. doi: 10.1016/j.ejmech.2025.117893.
Yu Yang  1 ,  Qian Yao  1 ,  Dan Song  1 ,  Kexin Tang  2 ,  Zijun Tang  3 ,  Mingxing Hu  4 ,  Yi Luo  5 ,  Yongmei Xie  6
Affiliations
  • 1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China.
  • 2. Department of Biology, Emory University, Atlanta, 30322, USA.
  • 3. Medical School of Guangxi University, Guangxi Key Laboratory of Special Biomedicine, Nanning, 530004, China.
  • 4. Department of Nuclear Medicine and Clinical Nuclear Medicine Research Lab, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
  • 5. Department of Orthopedics and Orthopaedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
  • 6. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China. Electronic address: [email protected].
PMID: 40578254 DOI: 10.1016/j.ejmech.2025.117893
Abstract

Fms-like tyrosine kinase 3 (FLT3) is a type III receptor tyrosine kinase expressed in hematopoietic progenitor cells and in most AML cell lines. Pharmacological inhibition of FLT3 enzymatic function is now a well-established strategy for the treatment of patients with these malignancies. Herein, we report the discovery and characterization of a FLT3 degrader A2. By design, A2 also mediates the degradation of Transcription Factors GSPT1 and IKZF1/3 through molecular glue interactions with the Cereblon E3 ubiquitin Ligase complex. Importantly, A2 exhibited significantly enhanced antiproliferative activity against drug-resistant AML cells compared to Gilteritinib (MV-4-11: IC50 = 1.67 ± 0.14 nM vs IC50 = 6.52 ± 1.20 nM). Furthermore, A2 with the rigid linker demonstrated improved some pharmacokinetic properties such as half-life (T1/2), which were achieved through rational design. Overall, A2 achieves concurrent degradation of these proteins by functioning as both PROTAC and molecular glue.

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