2. Academic Validation
  3. Development of Dual FLT3 and CHK1 PROTACs for the Treatment of AML

Development of Dual FLT3 and CHK1 PROTACs for the Treatment of AML

  • J Med Chem. 2025 Oct 23;68(20):21939-21961. doi: 10.1021/acs.jmedchem.5c02332.
Xuanmin Lian 1,  Yue Gao 2 3,  Wenjing Du 1,  Chengcheng Xu 2,  Xiaowu Dong 1,  Jinxin Che 1,  Yubo Zhou 2 3,  Jia Li 2 3,  Tao Liu 1 4 5
Affiliations

Affiliations

  • 1 Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Zijingang Campus, Hangzhou 310058, P. R. China.
  • 2 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, P. R. China.
  • 3 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China.
  • 4 National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou 310058, P. R. China.
  • 5 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, Zhejiang University, Hangzhou 310058, P. R. China.
PMID: 41043047 DOI: 10.1021/acs.jmedchem.5c02332
Abstract

FLT3 inhibitors (FLT3i) are effective for treating acute myeloid leukemia (AML), but acquired and adaptive resistance pose significant challenges. Therefore, finding a novel AML therapy that overcomes resistance is necessary. Proteolysis-targeting chimeras (PROTACs) are a new approach in drug discovery, offering a promising strategy for targeting FLT3 mutations in the development of effective anti-AML therapies. Our previous study found that simultaneously targeting FLT3 and Chk1 can upregulate p53 level and downregulate c-Myc level, thus overcoming adaptive resistance. We combined the merits of both PROTACs and dual targeting drugs to design a series of dual FLT3/CHK1 PROTACs. The optimal compound A28 effectively degraded FLT3 and Chk1 in a proteasome-dependent manner. Also, A28 potently inhibited FLT3 signaling, downregulated c-Myc, and upregulated p53 level. Further studies indicated that A28 had the potential to overcome acquired and adaptive resistance. Importantly, weekly intravenous administration of A28 sustained tumor growth suppression in MV-4-11 subcutaneous xenograft models.

Figures
Products