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A NRAS mRNA G-quadruplex structure-targeting small-molecule ligand reactivating DNA damage response in human cancer cells for combination therapy with clinical PI3K inhibitors. | LitMetric

A NRAS mRNA G-quadruplex structure-targeting small-molecule ligand reactivating DNA damage response in human cancer cells for combination therapy with clinical PI3K inhibitors.

Int J Biol Macromol

State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon 999077, Hong Kong, China. Electronic address:

Published: November 2024

AI Article Synopsis

Article Abstract

The Neuroblastoma RAS (NRAS) oncogene homologue plays crucial roles in diverse cellular processes such as cell proliferation, survival, and differentiation. Several strategies have been developed to inhibit NRAS or its downstream effectors; however, there is no effective drug available to treat NRAS-driven cancers and thus new approaches are needed to be established. The mRNA sequence expressing NRAS containing several guanine(G)-rich regions may form quadruplex structures (G4s) and regulate NRAS translation. Therefore, targeting NRAS mRNA G4s to repress NRAS expression at translational level with ligands may be a feasible strategy against NRAS-driven cancers but it is underexplored. We reported herein a NRAS mRNA G4-targeting ligand, B3C, specifically localized in cytoplasm in HeLa cells. It effectively downregulates NRAS proteins, reactivates the DNA damage response (DDR), causes cell cycle arrest in G/M phase, and induces apoptosis and senescence. Moreover, combination therapy with NARS mRNA G4-targeting ligands and clinical PI3K inhibitors for cancer cells inhibition treatment is unexplored, and we demonstrated that B3C combining with PI3Ki (pictilisib (GDC-0941)) showed potent antiproliferation activity against HeLa cells (IC = 1.03 μM (combined with 10 μM PI3Ki) and 0.42 μM (combined with 20 μM PI3Ki)) and exhibited strong synergistic effects in inhibiting cell proliferation. This study provides new insights into drug discovery against RAS-driven cancers using this conceptually new combination therapy strategy.

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Source
http://dx.doi.org/10.1016/j.ijbiomac.2024.135308DOI Listing

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