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Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
A CK2-targeted Pt(IV) prodrug to disrupt DNA damage response
Feihong Chen1, Xiaochao Huang1, Mian Wu1
1Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
Abstract:
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.
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