Structural optimization of non-nucleoside DNA methyltransferase inhibitor as anti-cancer agent

Area of Science:

• Epigenetics and Cancer Biology
• Medicinal Chemistry and Drug Discovery

Background:

• DNA methyltransferase 1 (DNMT1) inhibition can reverse cancer malignancy by restoring silenced tumor suppressor genes.
• Current DNMT1 inhibitors (decitabine, azacitidine) are nucleoside analogs susceptible to rapid enzymatic inactivation, complicating epigenetic dosing.
• Non-nucleoside inhibitors offer a potential strategy to overcome the limitations of current therapies.

Purpose of the Study:

• To identify novel non-nucleoside compounds that inhibit DNA methyltransferase 1 (DNMT1) activity and expression.
• To optimize lead compounds for improved potency in inhibiting cancer cell proliferation and DNMT1 levels.

Main Methods:

• A high-throughput PCR-based site-specific chromatin condensation assay was employed to screen a library of 5120 small molecules.
• Initial screening identified a compound that reactivated Cyclin-Dependent Kinase Inhibitor 2A (CDKN2A) in myeloma cells and suppressed DNMT1.
• Lead optimization involved generating 26 analogs, with activity assessed by lung cancer cell proliferation and DNMT1 expression.

Main Results:

• A novel compound was identified that reactivated the tumor suppressor gene CDKN2A and suppressed DNMT1 expression in myeloma cells.
• Lead optimization yielded 26 analogs, two of which demonstrated a two-fold improvement in growth-inhibiting potency against lung cancer cells.
• These optimized derivatives also significantly decreased DNMT1 protein levels in lung cancer cells.

Conclusions:

• Non-nucleoside compounds targeting DNMT1 represent a promising therapeutic avenue for cancer treatment.
• The identified derivatives show potential for improved efficacy and pharmacokinetics compared to existing nucleoside inhibitors.
• Further development of these DNMT1 inhibitors could lead to novel epigenetic therapies for various cancers.