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  3. Inhibition of ABCG2 by SCO-101 Enhances Chemotherapy Efficacy in Cancer

Inhibition of ABCG2 by SCO-101 Enhances Chemotherapy Efficacy in Cancer

  • Int J Mol Sci. 2025 Apr 17;26(8):3790. doi: 10.3390/ijms26083790.
Anamarija Pfeiffer 1 2,  Luca Di Leo 2,  Marc Baker Bechmann 2,  Mubeen Nawabi 3,  Sophie Ambjørner 4,  Diba Ardeshir-Larijani 2 4,  Louise Thybo Colstrup 2 4,  Signe Vedel Borchert 5,  Lasse Saaby 6 7,  Birger Brodin 7,  Michael Gajhede 4,  Xamuel Loft Lund 4 8,  Martina Čečková 9,  Nils Brünner 2 4,  Jan Stenvang 2 4
Affiliations

Affiliations

  • 1 Biognosys AG, 8952 Schlieren, Switzerland.
  • 2 Scandion Oncology A/S, Symbion, 2100 Copenhagen, Denmark.
  • 3 Genmab A/S, Carl Jacobsens Vej 30, 2500 Valby, Denmark.
  • 4 Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark.
  • 5 Department of Science and Environment, Roskilde University, 4000 Roskilde, Denmark.
  • 6 Bioneer A/S, Kogle Alle 2, 2970 Hørsholm, Denmark.
  • 7 Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark.
  • 8 Institut Laue-Langevin, 71 Avenue de Martyrs, 38042 Grenoble, France.
  • 9 Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic.
PMID: 40332396 DOI: 10.3390/ijms26083790
Abstract

Chemotherapy resistance, particularly multidrug resistance (MDR), remains a significant barrier to effective Cancer treatment, leading to high mortality rates. The development of novel therapeutic strategies targeting key molecular mechanisms to counteract drug resistance is thus an urgent clinical need. In this study, we evaluated the potential of the small molecule SCO-101 to restore chemotherapy sensitivity in drug-resistant Cancer cells. Using in silico and in vitro models such as molecular docking, cell viability, colony formation, dye efflux, transporter assays and chemotherapy retention, we assessed the impact of SCO-101 on drug retention and response in several drug-resistant Cancer cells. SCO-101 was found to inhibit the activity of breast Cancer resistance protein (BCRP/ABCG2) and UDP Glucuronosyltransferase Family 1 Member A1 (UGT1A1), two key proteins involved in drug resistance by cellular drug excretion and drug metabolism. Our results demonstrate that inhibition of these proteins by SCO-101 leads to increased intracellular drug accumulation, enhancing the cytotoxic effects of chemotherapy agents. Additionally, we identified a strong correlation between high ABCG2 expression and MDR in non-drug-resistant models, where cells exhibiting elevated ABCG2 levels displayed chemotherapy resistance, which was effectively reversed by SCO-101 co-treatment. These findings highlight the therapeutic potential of SCO-101 in overcoming MDR by inhibiting drug efflux mechanisms and metabolism, thereby enhancing chemotherapy efficacy. SCO-101 is currently undergoing clinical trials as an orally administered drug and is considered a promising strategy for improving Cancer treatment outcomes in patients with drug-resistant tumors.

Keywords

ABCG2; BCRP; SCO-101; UGT1A1; cancer multidrug resistance.

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