2. Academic Validation
  3. Discovery of Ruthenium(II) Metallocompound and Olaparib Synergy for Cancer Combination Therapy

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

  • J Med Chem. 2023 May 15. doi: 10.1021/acs.jmedchem.3c00322.
Nur Aininie Yusoh 1,  Paul R Tiley 2,  Steffan D James 2,  Siti Norain Harun 3,  Jim A Thomas 4,  Norazalina Saad 1,  Ling-Wei Hii 5,  Suet Lin Chia 1 6,  Martin R Gill 2,  Haslina Ahmad 1 3
Affiliations

Affiliations

  • 1 UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, UPM, 43400 Serdang, Selangor, Malaysia.
  • 2 Department of Chemistry, Faculty of Science and Engineering, Swansea University, Swansea SA2 8PP, U.K.
  • 3 Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, UPM, 43400 Serdang, Selangor, Malaysia.
  • 4 Department of Chemistry, University of Sheffield, Sheffield S3 7HF, U.K.
  • 5 Center for Cancer and Stem Cell Research, Development and Innovation (IRDI), Institute for Research, International Medical University, Kuala Lumpur 57000, Malaysia.
  • 6 Department of Microbiology, Faculty of Biotechnology and Biomolecular Science, Universiti Putra Malaysia, UPM, 43400 Serdang, Selangor, Malaysia.
PMID: 37185020 DOI: 10.1021/acs.jmedchem.3c00322
Abstract

Synergistic drug combinations can extend the use of poly(ADP-ribose) polymerase inhibitors (PARPi) such as Olaparib to BRCA-proficient tumors and overcome acquired or de novo drug resistance. To identify new 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-proficient triple-negative breast Cancer cells. This identified three hits: the natural product Curcumin and two ruthenium(II)-rhenium(I) polypyridyl metallomacrocycles. All combinations identified were effective in BRCA-proficient breast Cancer cells, including an Olaparib-resistant cell line, and spheroid models. Mechanistic studies indicated that synergy was achieved via DNA-damage enhancement and resultant Apoptosis. Combinations showed low cytotoxicity toward non-malignant breast epithelial cells and low acute and developmental toxicity in zebrafish embryos. This work identifies RPC metallomacrocycles as a novel class of agents for Cancer combination therapy and provides a proof of concept for the inclusion of metallocompounds within drug synergy screens.

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