Simultaneous Inhibition of PARP-1 and CK2α by Novel Benzothieno[3,2- d ]pyrimidin-4(1 H )-one Derivatives: A Promising Strategy to Combat Homologous Recombination Deficiency-Independent Tumors and Metastasis

Abstract Poly(ADP-ribose) polymerase 1 (PARP-1) inhibitors yield robust clinical benefits yet only work for homologous recombination deficiency (HRD) patients. To expand their utility and resolve clinical drawbacks, we synthesized dual PARP-1/casein kinase II alpha (CK2α) inhibitors built on benzofuran/benzothieno[3,2-d]pyrimidin-4(1H)-one cores with methyl (Z)-carbamohydrazonothioate pharmacophores. Among them, NJT-12 exhibited the optimal activity, with IC50 values of 3.40 and 4.31 nM against PARP-1 and CK2α. In non-HRD A2780 cells, NJT-12 modulates the Akt1Ser129-GSK-3βSer9-Wnt/β-catenin pathway to regulate cancer cell stemness and suppress cell invasion and metastasis. In SD rats, NJT-12 had an oral half-life of 3.92 h and an oral bioavailability of 44.0%. At 100 mg/kg in the A2780 xenograft mice models, it achieved 79.66% tumor growth inhibition with no obvious toxicity. This study provides novel strategies and key molecular tools for the design, development and biological research of PARP-1/CK2α dual-target inhibitors, and NJT-12 with excellent pharmacological properties deserves further exploration.