Identification of ATP-Competitive Human CMG Helicase Inhibitors for Cancer Intervention that Disrupt CMG-Replisome...

Area of Science:

• Molecular Biology
• Biochemistry
• Oncology

Background:

• The human CMG helicase (Cdc45-MCM-GINS) is a promising target for anticancer therapies due to tumor-specific vulnerabilities.
• CMG activity is crucial for cellular recovery from replicative stress, including chemotherapy-induced damage.

Purpose of the Study:

• To develop and characterize novel inhibitors of the CMG helicase (CMGi) for potential anticancer applications.
• To elucidate the mechanism of action of CMGi/MCMi and their selective toxicity towards cancer cells.

Main Methods:

• Orthogonal biochemical screening to identify CMG inhibitors (CMGi).
• Structure-activity relationship studies, in silico docking, and synthetic compound testing.
• Biologic assays to assess cell growth inhibition, DNA replication, and molecular mechanisms.

Main Results:

• Identified CMGi that inhibit CMG helicase ATPase and helicase activities via ATP-competitive binding within MCM subunits.
• CMGi/MCMi were shown to block CMG assembly, destabilize replisome components, and induce DNA damage.
• CMGi/MCMi exhibited selective toxicity against solid tumor cells with K-Ras mutations, leading to cell death.

Conclusions:

• CMG inhibitors (CMGi), also termed MCM complex inhibitors (MCMi), represent a new class of anticancer agents.
• These compounds target the CMG helicase, inducing DNA damage and selective tumor cell toxicity through novel mechanisms.
• CMGi/MCMi provide a foundation for developing small-molecule drugs targeting the CMG helicase for cancer treatment.