Design, synthesis and biological evaluation of 3-amino-6-(2-hydroxyphenyl)pyridazin-4-aryl derivatives as SMARCA2/4 degraders

  • Eur J Med Chem. 2025 Jun 5:290:117521. doi: 10.1016/j.ejmech.2025.117521.
Tianqiong Yang  1 ,  Wei Wei  1 ,  Qi Zhang  1 ,  Xin Chen  2 ,  Kaiyan Xu  2 ,  Xingping Su  1 ,  Lin Yue  1 ,  Jiuyu Gao  1 ,  Ningyu Wang  2 ,  Yu Cao  1 ,  Luoting Yu  3 ,  Zhihao Liu  4
Affiliations
  • 1. Department of Emergency Medicine and Laboratory of Emergency Medicine, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 2. School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China.
  • 3. Department of Emergency Medicine and Laboratory of Emergency Medicine, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China; Children's Medicine Key Laboratory of Sichuan Province, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
  • 4. Department of Emergency Medicine and Laboratory of Emergency Medicine, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
PMID: 40138993 DOI: 10.1016/j.ejmech.2025.117521
Abstract

SMARCA2/4, a pair of mutually exclusive core catalytic subunits of the chromatin remodeling complex SWI/SNF, play essential roles in regulating gene transcription. Given the pivotal role of SMARCA2/4 in sustaining the oncogenic transcription program and promoting proliferation in acute myeloid leukemia (AML), the development of non-selective degraders holds practical therapeutic implications. Herein, we designed and synthesized a series of proteolysis-targeting chimeras (PROTACs) by conjugating the VHL ligand to a SMARCA2/4 bromodomain ligand, 2-(6-amino-5-phenylpyridazin-3-yl)phenol, using various linkers. Preliminary evaluations identified A11 as the most potent molecule that efficiently degraded SMRACA2 (DC50 = 3.0 nM, Dmax = 98 %) and SMARCA4 (DC50 = 4.0 nM, Dmax = 98 %). A11 significantly inhibited the proliferation of hematological Cancer cell lines, including MV-4-11, MOLM-13 and SU-DHL-4. It decreased the levels of SMARCA2/4 through the ubiquitin-proteasome system. Global proteome analysis revealed that A11 was able to selectively target and degrade SMARCA2/4. Additionally, A11 caused cell cycle arrest at the G0/G1 phase and induced cell Apoptosis in MV-4-11 and MOLM-13 cells. It also blocked the oncogenic activity of MYC and Other disease-related genes in AML cells. Overall, our data clarified that A11 is a promising SMARCA2/4 degrader for Cancer therapy, which is worthy of further evaluation.

Keywords
Acute myeloid leukemia; Degrader; SMARCA2/4; Structure-activity relationship.
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