Original ArticleA CK2-targeted Pt(IV) prodrug to disrupt DNA damage response

•A novel CK2-targeted Pt(IV) prodrug (Cx-platin) was designed and prepared.•Cx-platin exhibited stronger antitumor activity and lower toxicity than cisplatin.•Mechanism study reveals Cx-platin can suppress CK2-dependent MDC1 of DSBs repair.

A Pt(IV) prodrug, Cx-platin, containing CX-4945 (a CK2 inhibitor) as an axial ligand was designed and prepared by targeting CK2 to disrupt DNA damage response. In vitro study indicated that Cx-platin had superior cytotoxicity to cisplatin against a number of cancer cell lines with distinct CK2-expressed levels, caused CK2-overexpressed cancer cells death via suppressing CK2-mediated DNA damage repair and reversed cisplatin resistance. Mechanistic investigation suggested that the potent antitumor activity of Cx-platin resulted from its major suppression of CK2-phosphorylated MDC1 to combine FHA domain of aprataxin to DNA double strand breaks (DSBs) caused by improved cellular uptakes of Pt and ATM deactivation. Further in vivo tests exhibited that Cx-platin displayed high tumor inhibition rates, increased weight gain, and hardly toxicity effects in contrast to cisplatin.

Graphical abstractA model for CK2-targeting mechanism of the Pt(IV) prodrug in circumventing cisplatin-induced resistance in cancer cells.Download high-res image (140KB)Download full-size image