Design, synthesis and biological studies of survivin dimerization modulators that prolong mitotic cycle

Area of Science:

• Molecular Biology
• Cancer Research
• Drug Discovery

Background:

• Survivin, an inhibitor of apoptosis protein (IAP), is crucial for cell division and survival.
• Elevated survivin levels in cancer patients correlate with disease aggressiveness and treatment resistance.
• Survivin functions as part of the chromosomal passenger complex (CPC), interacting with borealin and INCENP at its dimerization interface.

Purpose of the Study:

• To investigate the disruption of survivin's dimerization interface using small molecules as a strategy to inhibit cancer cell proliferation.
• To develop novel survivin dimerization modulators for potential therapeutic applications in cancer treatment.

Main Methods:

• Utilized computational modeling to refine survivin dimerization interface interactions.
• Designed and synthesized novel survivin modulators, including LLP3 and LLP9.
• Assessed the effects of LLP3 and LLP9 on cell cycle progression and mitotic defects in proliferating human umbilical vein endothelial cells (HUVEC) and prostate cancer cells (PC3).

Main Results:

• Identified potent survivin modulators, LLP3 and LLP9.
• LLP3 and LLP9, at concentrations of 50-100 nM, induced significant delays in mitotic progression.
• Observed major mitotic defects in HUVEC and PC3 cancer cells treated with LLP3 and LLP9.

Conclusions:

• Disrupting the survivin dimerization interface with small molecules is a viable strategy for cancer therapy.
• LLP3 and LLP9 demonstrate potential as therapeutic agents by inhibiting cancer cell proliferation and inducing mitotic abnormalities.
• Further development of survivin dimerization modulators could lead to novel treatments that sensitize cancer cells to existing therapies.