2. Academic Validation
  3. Discovery of pyridoquinoxaline-based new P-gp inhibitors as coadjutant against Multi Drug Resistance in cancer

Discovery of pyridoquinoxaline-based new P-gp inhibitors as coadjutant against Multi Drug Resistance in cancer

  • Eur J Med Chem. 2024 Jul 7:276:116647. doi: 10.1016/j.ejmech.2024.116647.
Roberta Ibba 1,  Simona Sestito 2,  Francesca Alessandra Ambrosio 3,  Emanuela Marchese 4,  Giosuè Costa 5,  Francesco Paolo Fiorentino 6,  Fabio Fusi 7,  Irene Marchesi 8,  Beatrice Polini 9,  Grazia Chiellini 10,  Stefano Alcaro 11,  Sandra Piras 12,  Antonio Carta 13
Affiliations

Affiliations

  • 1 Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100, Sassari, Italy. Electronic address: ribba@uniss.it.
  • 2 Department of Chemical, Physical, Mathematical and Natural Sciences, University of Sassari, 07100, Sassari, Italy. Electronic address: ssestito@uniss.it.
  • 3 Department of Health Sciences, University "Magna Græcia" of Catanzaro, Campus "S. Venuta", 88100, Catanzaro, Italy. Electronic address: ambrosio@unicz.it.
  • 4 Department of Health Sciences, University "Magna Græcia" of Catanzaro, Campus "S. Venuta", 88100, Catanzaro, Italy. Electronic address: e.marchese@unicz.it.
  • 5 Department of Health Sciences, University "Magna Græcia" of Catanzaro, Campus "S. Venuta", 88100, Catanzaro, Italy; Net4Science Academic Spin-Off, University "Magna Græcia" of Catanzaro, Campus "S. Venuta", 88100, Catanzaro, Italy. Electronic address: gcosta@unicz.it.
  • 6 Kitos Biotech Srls, Tramariglio, Alghero, SS, Italy. Electronic address: fpfiorentino@kitosbiotech.org.
  • 7 Department of Biotechnologies, Chemistry and Pharmacy, University of Siena, 53100, Siena, Italy. Electronic address: fabio.fusi@unisi.it.
  • 8 Kitos Biotech Srls, Tramariglio, Alghero, SS, Italy. Electronic address: imarchesi@kitosbiotech.org.
  • 9 Department of Pathology, University of Pisa, 56100, Pisa, Italy. Electronic address: beatrice.polini@farm.unipi.it.
  • 10 Department of Pathology, University of Pisa, 56100, Pisa, Italy. Electronic address: grazia.chiellini@unipi.it.
  • 11 Department of Health Sciences, University "Magna Græcia" of Catanzaro, Campus "S. Venuta", 88100, Catanzaro, Italy; Net4Science Academic Spin-Off, University "Magna Græcia" of Catanzaro, Campus "S. Venuta", 88100, Catanzaro, Italy. Electronic address: alcaro@unicz.it.
  • 12 Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100, Sassari, Italy. Electronic address: piras@uniss.it.
  • 13 Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100, Sassari, Italy. Electronic address: acarta@uniss.it.
PMID: 38981337 DOI: 10.1016/j.ejmech.2024.116647
Abstract

Multi-drug resistance (MDR) is a serious challenge in contemporary clinical practice and is mostly responsible for the failure of Cancer medication therapies. Several experimental evidence links MDR to the overexpression of the drug efflux transporter P-gp, therefore, the discovery of novel P-glycoprotein inhibitors is required to treat or prevent MDR and to improve the absorption of chemotherapy drugs via the gastrointestinal system. In this work, we explored a series of novel pyridoquinoxaline-based derivatives designed from parental compounds, previously proved active in enhancing Anticancer drugs in MDR nasopharyngeal carcinoma (KB). Among them, derivative 10d showed the most potent and selective inhibition of Fluorescent Dye efflux, if compared to reference compounds (MK-571, Novobiocin, Verapamil), and the highest MDR reversal activity when co-administered with the chemotherapeutic agents Vincristine and Etoposide, at non-cytotoxic concentrations. Molecular modelling predicted the two compound 10d binding mode in a ratio of 2:1 with the target protein. No cytotoxicity was observed in healthy microglia cells and off-target investigations showed the absence of CAV1.2 channel blockade. In summary, our findings indicated that 10d could potentially be a novel therapeutic coadjutant by inhibiting P-gp transport function in vitro, thereby reversing Cancer multidrug resistance.

Keywords

ADME prediction; Cancer; Docking studies; Multi-drug resistance; P-glycoprotein; Quinoxaline derivatives.

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