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

ABSTRACT: The human CMG helicase (Cdc45-MCM-GINS) is a novel target for anti-cancer therapy due to tumor-specific weaknesses in CMG function induced by oncogenic changes and the need for CMG function during recovery from replicative stresses such as chemotherapy. Here, we developed an orthogonal biochemical screening approach and identified selective CMG inhibitors (CMGi) that inhibit ATPase and helicase activities in an ATP-competitive manner at low micromolar concentrations. Structure-activity information and in silico docking indicate that CMGi occupy ATP binding sites and channels within MCM subunits leading to the ATP clefts, which are likely used for ATP/ADP ingress or egress. CMGi inhibit cell growth and DNA replication using multiple molecular mechanisms. CMGi block helicase assembly

SUBMITTER: Xiang S 

PROVIDER: S-EPMC10441460 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature