Novel telomere-targeting dual-pharmacophore dinucleotide prodrugs for anticancer therapy

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Telomerase is an attractive therapeutic target due to its expression in most cancer cells. This study focuses on harnessing the potential of telomerase to alter telomeres as a therapeutic modality. We designed and synthesized divalent dinucleotide prodrugs comprised of 6-thio-2'-deoxyguanosine (6-thio-dG; THIO) and 5-fluoro-2'-deoxyuridine (5-FdU) nucleosides. Although dinucleotides containing 5-FdU pharmacophores showed better activity in vitro versus compounds containing only THIO pharmacophores, we observed greater activity for THIO-containing compounds in vivo. The homopurine compounds MAIA-2022-12 and MAIA-2021-20, with two 6-thio-dG pharmacophores, linked by 3', 5'- and 5', 5'-phosphodiester bonds, respectively, demonstrated the greatest anticancer efficacy among the compounds tested and induced host immune-memory responses in vivo. The sequential combination of MAIA-2022-12 or MAIA-2021-20 with the immune anti-PD-1 or anti-PD-L1 checkpoint inhibitors demonstrated superior anticancer efficacy compared with the corresponding monotherapies. We conclude that MAIA-2022-12 and MAIA-2021-20 are promising candidates for future preclinical and potential clinical studies.

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