2. Academic Validation
  3. Discovery of Potent Dual PROTAC Degraders Targeting BET-Kinase To Overcome FLT3 Inhibitor Resistance

Discovery of Potent Dual PROTAC Degraders Targeting BET-Kinase To Overcome FLT3 Inhibitor Resistance

  • J Med Chem. 2025 Aug 28;68(16):17303-17322. doi: 10.1021/acs.jmedchem.5c00831.
Qiuping Xiang 1 2,  Yujie Sun 1 2,  Hui Hua 1 2,  Mengdie Hu 3,  Xiaomei Li 1 2,  Manyu Guo 3,  Le Niu 3,  Zhang Zhang 4,  Ting Cai 1 2,  Dongsheng Zhu 3 5
Affiliations

Affiliations

  • 1 Ningbo No.2 Hospital, Ningbo 315010, China.
  • 2 Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo 315000, China.
  • 3 Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
  • 4 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou 510632, China.
  • 5 Department of Urology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing 210003, China.
PMID: 40764262 DOI: 10.1021/acs.jmedchem.5c00831
Abstract

FMS-like tyrosine kinase 3 (FLT3) is a validated therapeutic target in acute myeloid leukemia (AML). However, numerous single-agent FLT3 or multitarget inhibitors fail to achieve complete and sustained suppression of FLT3 signaling due to the development of drug resistance. Herein, we report the design, synthesis, and evaluation of a novel series of dual BET-kinase degraders targeting FLT3, JAK2, and BRD4. Optimization led to 13e, which efficiently degraded FLT3, JAK2, and BRD4 in MV4;11 cells with DC50 values of 5.23, 0.678, and 1.17 nM, respectively. Mechanistic studies confirmed cereblon- and proteasome-dependent degradation. 13e significantly inhibited MV4;11 cell proliferation and demonstrated promising antitumor activity in an MV4;11 xenograft model. Additionally, 13e showed enhanced antiproliferative activity against FLT3 mutant-transformed Ba/F3 cells, indicating its potential to overcome resistance. Collectively, 13e represents a highly promising FLT3/JAK2/BRD4 Degrader with potent antileukemic activity and the ability to overcome resistance associated with current FLT3 inhibitors.

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