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
  • 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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