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

ABSTRACT: The human CMG helicase (Cdc45-MCM-GINS) is a novel target for anticancer therapy. Tumor-specific weaknesses in the CMG are caused by oncogene-driven changes that adversely affect CMG function, and CMG activity is required for recovery from replicative stresses such as chemotherapy. Herein, we developed an orthogonal biochemical screening approach and identified CMG inhibitors (CMGi) that inhibit ATPase and helicase activities in an ATP-competitive manner at low micromolar concentrations. Structure-activity information, in silico docking, and testing with synthetic chemical compounds indicate that CMGi require specific chemical elements and occupy ATP-binding sites and channels within minichromosome maintenance (MCM) subunits leading to the ATP clefts, which are likely used for ATP/ADP ingr

SUBMITTER: Xiang S 

PROVIDER: S-EPMC11532780 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature