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首页> 外文期刊>Journal of Medicinal Chemistry >Discovery of Ruthenium(II) Metallocompound and Olaparib Synergy for Cancer Combination Therapy
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Discovery of Ruthenium(II) Metallocompound and Olaparib Synergy for Cancer Combination Therapy

机译：Discovery of Ruthenium(II) Metallocompound and Olaparib Synergy for Cancer Combination Therapy

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Synergistic drug combinations can extend the use of poly-(ADP-ribose)polymerase inhibitors (PARPi) such as Olaparib to BRCA-proficienttumors and overcome acquired or de novo drug resistance. To identifynew synergistic combinations for PARPi, we screened a "micro-library"comprising a mix of commercially available drugs and DNA-binding ruthenium-(II)polypyridyl complexes (RPCs) for Olaparib synergy in BRCA-proficienttriple-negative breast cancer cells. This identified three hits: thenatural product Curcumin and two ruthenium-(II)-rhenium-(I) polypyridylmetallomacrocycles. All combinations identified were effective inBRCA-proficient breast cancer cells, including an Olaparib-resistantcell line, and spheroid models. Mechanistic studies indicated thatsynergy was achieved via DNA-damage enhancement and resultant apoptosis.Combinations showed low cytotoxicity toward non-malignant breast epithelialcells and low acute and developmental toxicity in zebrafish embryos.This work identifies RPC metallomacrocycles as a novel class of agentsfor cancer combination therapy and provides a proof of concept forthe inclusion of metallocompounds within drug synergy screens.

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