Die Pharmazie is published by IMR Press from Volume 81 Issue 1 (2026). Previous articles were published by another publisher under the CC-BY licence, and they are hosted by IMR Press on imrpress.com as a courtesy and upon agreement.
Design, synthesis, and biological evaluation of isoquinolin-1(2H)-one derivates as tankyrase-1/2 inhibitors
Haiping Yao 1, Yanyan Wang 2, Mo Jiangwen 2, Yan Peng 2, Zhu Wang 3
Affiliations
Article Info
1 Department of Pharmacy, The First College of Clinical Medical Science, China Three Gorges University & Yichang Central People's Hospital, Yichang; Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation
2 Department of Pharmacy, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P. R. China
3 Department of Pediatrics, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P. R. China
Abstract
To investigate structure-activity relationships of tankyrase (TNKS) inhibitors, twelve new derivatives of isoquinolin-1(2 H )-one were designed and synthesized, and biological assessments were conducted. Several potent TNKS inhibitors with single- or double-digit nanomolar IC50 values were identified using enzymatic assays. Compound 11c was the most potent compound of this series and inhibited TNKS1 and TNKS2 at an IC50 of 0.009 and 0.003 μM, respectively, and showed an IC50 of 0.029 μM in a DLD-1 SuperTopFlash assay. Molecular docking results showed that compound 11c occupied a unique subpocket and formed a hydrogen bond with Glu1138 of TNKS2, which was not consistent with the patterns of known TNKS inhibitors and thus warrants further research.