Discovery, Optimization, and Biological Evaluation of 2-Cyano-2-(9 H-xanthen-9-ylidene)acetamide Derivatives as ZNF207 Inhibitors for Anti-Glioma Therapy

  • J Med Chem. 2026 Apr 9;69(7):7594-7641. doi: 10.1021/acs.jmedchem.5c02857.
Mengkang Gao  1 ,  Jiayi Wang  2 ,  Youchen Wang  2 ,  Jiacheng Li  2 ,  Jie Feng  3 ,  Congying Gu  2 ,  Zhi Wang  2 ,  Xin Gong  2 ,  Wang Zhou  2 ,  Siheng Chen  2 ,  Xingyu Xia  2 ,  Xinying Tang  3 ,  Yong Yang  3 ,  Dayong Zhang  2 ,  Yushi Ding  4 ,  Menghan Zhang  3
Affiliations
  • 1. School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 2. School of Science, China Pharmaceutical University, Nanjing 211198, China.
  • 3. Institute of Translational Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211112, China.
  • 4. School of Modern Pharmaceutical Industry, China Pharmaceutical University, Nanjing 211112, China.
PMID: 41854173 DOI: 10.1021/acs.jmedchem.5c02857
Abstract

Zinc Finger Protein 207 (ZNF207) is highly expressed in glioma and represents a promising therapeutic target. Building on the reported inhibitor C16, we developed a novel derivative, TMLZ-G1, with improved stability and a removed chiral center. Subsequent optimization identified TMLZ-G46, which showed high affinity for ZNF207 (KD = 68 nM), potent antiproliferative activity against ZNF207-high glioma cells (IC50 = 0.93-2.07 μM), and strong inhibition of stemness (IC50 = 0.34-0.58 μM). TMLZ-G46 suppressed colony formation, migration, and invasion; induced cell cycle arrest and apoptosis; and displayed favorable pharmacokinetics with 68.1% oral bioavailability, brain penetration, and no P-glycoprotein efflux. In vivo, TMLZ-G46 achieved 83.7% tumor growth inhibition in subcutaneous glioblastoma (GBM) (grade IV) cell line-derived xenografts without detectable toxicity and significantly prolonged survival in an orthotopic GBM xenograft model, with efficacy comparable to temozolomide. These findings highlight TMLZ-G46 as a promising candidate for glioma therapy.

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