Mitotic arrest deficient 2-like protein 1–Cell division cycle protein 20 protein–protein interface (MAD2–CDC20 interface)

The Mitotic arrest deficient 2-like protein 1 (MAD2)–Cell division cycle protein 20 (CDC20) protein–protein interface is a critical regulatory junction within the spindle assembly checkpoint (SAC), a surveillance mechanism that ensures accurate chromosome segregation during mitosis. MAD2 exists in two conformational states, open (O-Mad2) and closed (C-Mad2); the latter binds directly to CDC20 to inhibit its ability to activate the anaphase-promoting complex/cyclosome (APC/C). This interaction is essential for delaying anaphase until all chromosomes are properly attached to the spindle, thereby preventing aneuploidy and maintaining genomic stability. In many cancers, CDC20 is overexpressed, leading to checkpoint evasion and uncontrolled proliferation, making the MAD2–CDC20 interface an attractive therapeutic target. Small molecule inhibitors like M2I-1 specifically disrupt this interface, preventing the formation of the mitotic checkpoint complex (MCC) and forcing premature mitotic exit. This disruption induces apoptosis in cancer cells, particularly when used in combination with traditional anti-mitotic drugs like taxanes. Targeting this interface offers a strategy to overcome drug resistance and improve the selectivity of anti-cancer treatments by directly modulating the cell cycle machinery.

Other names

MAD2-CDC20 interactionMAD2L1-CDC20 complexMitotic checkpoint complex (MCC) interfaceMAD2-CDC20 binding site

Disruption of the protein-protein interaction between MAD2 and CDC20, preventing the formation of the mitotic checkpoint complex (MCC) and leading to premature activation of the anaphase-promoting complex/cyclosome (APC/C).