Design, Synthesis, and Biological Evaluation of Apcin-Based CDC20 Inhibitors

Area of Science:

• Oncology
• Molecular Biology
• Medicinal Chemistry

Background:

• CDC20 is crucial for mitotic progression, and its overexpression in cancers like triple-negative breast cancer (TNBC) leads to cell cycle dysregulation and poor prognosis.
• Apcin, a known CDC20 inhibitor, has shown activity but requires synthesis involving controlled substances and exhibits high micromolar activity.

Purpose of the Study:

• To design and synthesize novel apcin-based CDC20 inhibitors.
• To improve the antitumor efficacy and synthetic accessibility of CDC20 inhibitors.
• To evaluate the efficacy and specificity of new inhibitors against TNBC cell lines.

Main Methods:

• Chemical synthesis of novel apcin analogs replacing pyrimidine with substituted thiazole groups.
• In vitro evaluation of inhibitor cytotoxicity using cell viability assays (IC50 determination) in MDA-MB-231 and MDA-MB-468 TNBC cell lines.
• Assessment of off-target effects via tubulin polymerization assays and analysis of apoptosis induction (Bim accumulation).

Main Results:

• Several novel apcin analogs demonstrated 5-10 fold improvement in activity over apcin, with IC50 values around 10 μM in TNBC cell lines.
• The synthesized inhibitors showed no significant off-target effects on tubulin polymerization.
• Treatment with the most potent inhibitors led to the accumulation of proapoptotic protein Bim in MDA-MB-468 cells.

Conclusions:

• The developed apcin-based CDC20 inhibitors are effective against TNBC cells with improved potency and synthetic accessibility.
• These novel compounds represent promising therapeutic candidates for targeting CDC20 in cancer treatment.
• Further development of inhibitor 22 is warranted for its potential in treating CDC20-driven diseases.