2. Academic Validation
  3. Design, synthesis and pharmacological evaluation of new SMARCA2 degraders bearing a furo[3,2-c]pyridazine scaffold

Design, synthesis and pharmacological evaluation of new SMARCA2 degraders bearing a furo[3,2-c]pyridazine scaffold

  • Eur J Med Chem. 2026 Apr 15:308:118675. doi: 10.1016/j.ejmech.2026.118675.
Jiaming Diao 1,  Hongyan Jing 2,  Xinyan Lin 1,  Yi Wang 3,  Yiting Lu 4,  Lan Xu 3,  Chaodong Xiong 1,  Ao Zhang 5,  Linghua Meng 2,  Xi Zhang 6,  Zilan Song 7
Affiliations

Affiliations

  • 1 Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China; National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, 800 Dongchuan Road, Minhang District, Shanghai, 200240, China.
  • 2 Division of Anti-tumor Pharmacology, State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3 Division of Anti-tumor Pharmacology, State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China.
  • 4 Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China; School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang, 325035, China.
  • 5 Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China; National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, 800 Dongchuan Road, Minhang District, Shanghai, 200240, China; School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang, 325035, China.
  • 6 Division of Anti-tumor Pharmacology, State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China. Electronic address: [email protected].
  • 7 Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China; National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, 800 Dongchuan Road, Minhang District, Shanghai, 200240, China. Electronic address: [email protected].
PMID: 41734590 DOI: 10.1016/j.ejmech.2026.118675
Abstract

As mutually exclusive catalytic ATPase subunits of the SWI/SNF chromatin remodeling complex, SMARCA2 and SMARCA4 play crucial roles in regulating gene transcription. Studies have revealed that SMARCA4-deficient cells exquisitely depend on SMARCA2 for survival, suggesting SMARCA2 is a promising synthetic lethal target in SMARCA4-deficient cancers. Herein, we reported the design, synthesis, and biological evaluation of a series of novel proteolysis targeting chimeras (PROTACs) of SMARCA2 bearing a novel furo[3,2-c]pyridazine scaffold. Among these compounds, compound 26 displayed an excellent SMARCA2 degradation efficiency with a DC50 value of 51 nM and potently inhibited SMARCA4-deficient Cancer cell growth. Compared with AU-15330, which has comparable degradation activity towards SMARCA2/4 (DC50: 42 nM vs 41 nM), compound 26 achieved a 5-fold selectivity towards SMARCA2. In NCI-H1944 xenograft model, 26 significantly reduced SMARCA2 protein levels in tumor tissue and inhibited tumor growth without obvious adverse events, indicating that compound 26 is a promising lead compound for further evaluation as potential treatment of SMARCA4-deficient cancers.

Keywords

PROTAC; SMARCA2; SMARCA4-Deficient cancer; Synthetic lethality.

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