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

Area of Science:

• Oncology
• Pharmacology
• Immunology

Background:

• Telomerase is highly expressed in most cancer cells, making it a promising therapeutic target.
• Altering telomere length through telomerase inhibition is a potential anti-cancer strategy.

Purpose of the Study:

• To design and synthesize novel divalent dinucleotide prodrugs targeting telomerase.
• To evaluate the in vitro and in vivo anticancer efficacy of these novel compounds.
• To investigate the potential of these compounds in combination with immune checkpoint inhibitors.

Main Methods:

• Synthesis of divalent dinucleotide prodrugs containing 6-thio-2 -deoxyguanosine (THIO) and 5-fluoro-2 -deoxyuridine (5-FdU) pharmacophores.
• In vitro and in vivo evaluation of anticancer activity.
• Assessment of immune-memory responses induced by the compounds.
• Combination studies with anti-PD-1 and anti-PD-L1 checkpoint inhibitors.

Main Results:

• Dinucleotides with THIO pharmacophores showed greater in vivo activity than those with 5-FdU.
• Homopurine compounds MAIA-2022-12 and MAIA-2021-20 exhibited the highest anticancer efficacy and induced immune-memory responses.
• Sequential combination of MAIA-2022-12 or MAIA-2021-20 with anti-PD-1/anti-PD-L1 inhibitors resulted in superior anticancer efficacy compared to monotherapy.

Conclusions:

• MAIA-2022-12 and MAIA-2021-20 are potent anticancer agents targeting telomerase.
• These compounds demonstrate immunomodulatory effects, enhancing anti-tumor responses.
• The combination of these novel agents with immune checkpoint inhibitors holds significant therapeutic potential for cancer treatment.