2. Academic Validation
  3. Discovery of FLT3-targeting PROTACs with potent antiproliferative activity against acute myeloid leukemia cells harboring FLT3 mutations

Discovery of FLT3-targeting PROTACs with potent antiproliferative activity against acute myeloid leukemia cells harboring FLT3 mutations

  • Eur J Med Chem. 2024 Feb 14:268:116237. doi: 10.1016/j.ejmech.2024.116237.
Zhijie Wang 1,  Xun Lu 2,  Canlin Liu 2,  Fei Huang 2,  Tao Lu 3,  Yadong Chen 4,  Lifei Liu 5,  Shuai Lu 6
Affiliations

Affiliations

  • 1 ShenZhen Hospital, Southern Medical University, Shenzhen, 518000, PR China; School of Science, China Pharmaceutical University, Nanjing, 211198, PR China.
  • 2 School of Science, China Pharmaceutical University, Nanjing, 211198, PR China.
  • 3 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, PR China.
  • 4 Laboratory of Molecular Design and Drug Discovery, China Pharmaceutical University, Nanjing, 211198, PR China. Electronic address: chenyadong@gmail.com.
  • 5 Department of Infectious Disease, Children's Hospital of Nanjing Medical University, Nanjing, 210008, PR China. Electronic address: 61085@163.com.
  • 6 School of Science, China Pharmaceutical University, Nanjing, 211198, PR China. Electronic address: lu_shuai@cpu.edu.cn.
PMID: 38387337 DOI: 10.1016/j.ejmech.2024.116237
Abstract

Acute myeloid leukemia (AML) patients harboring Fms-like tyrosine kinase 3 (FLT3) mutations often suffer from poor prognosis and relapse. Targeted protein degradation utilizing proteolysis targeting chimeras (PROTACs) is considered as a novel therapeutic strategy in drug discovery and may be a promising modality to target FLT3 mutations for the development of potent anti-AML drugs. Herein, a kind of FLT3-targeting PROTACs was rationally developed based on a FLT3 Inhibitor previously reported by us. The representative compound 35 showed potent and selective antiproliferative activities against AML cells harboring FLT3 mutations. Western blot assay demonstrated that compound 35 effectively induced the degradation of FLT3-ITD and decreased the phosphorylation levels of FLT3-ITD, Akt, STAT5 and ERK in MV4-11 cells in a dose-dependent manner. Flow cytometry analysis illustrated that compound 35 strongly induced Apoptosis and cell cycle arrest in MV4-11 cells in a dose-dependent manner. Moreover, compound 35 displayed favorable metabolic stability in in-vitro liver microsomes studies. Comparative molecular dynamic (MD) simulation studies further elucidated the underlying mechanism of compound 35 to stabilize the dynamic ensemble of the FLT3-compound 35-cereblon (CRBN) ternary complex. Taken together, compound 35 could serve as a lead molecule for developing FLT3 degraders against AML.

Keywords

AML; FLT3 mutation; MD simulation; PROTAC.

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