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

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

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: yuluot@scu.edu.cn.
  • 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: liuzhihao@scu.edu.cn.
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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