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.

Biognosys AG 8952 Schlieren Switzerland

Bioneer A S Kogle Alle 2 2970 Hørsholm Denmark

Department of Drug Design and Pharmacology Faculty of Health and Medical Sciences University of Copenhagen 2100 Copenhagen Denmark

Department of Pharmacology and Toxicology Faculty of Pharmacy in Hradec Kralove Charles University Akademika Heyrovskeho 1203 500 05 Hradec Kralove Czech Republic

Department of Pharmacy Faculty of Health and Medical Sciences University of Copenhagen 2100 Copenhagen Denmark

Department of Science and Environment Roskilde University 4000 Roskilde Denmark

Genmab A S Carl Jacobsens Vej 30 2500 Valby Denmark

Institut Laue Langevin 71 Avenue de Martyrs 38042 Grenoble France

Scandion Oncology A S Symbion 2100 Copenhagen Denmark

Zobrazit více v PubMed

Bray F., Laversanne M., Sung H., Ferlay J., Siegel R.L., Soerjomataram I., Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2024;74:229–263. doi: 10.3322/caac.21834. PubMed DOI

International Agency for Research on Cancer Estimated Number of Deaths from 2022 to 2050, Both Sexes, Age [0–85+] [(accessed on 20 January 2025)]. Available online: https://gco.iarc.fr/tomorrow/en/dataviz/isotype?types=1&single_unit=500000&years=2050.

Meads M.B., Gatenby R.A., Dalton W.S. Environment-mediated drug resistance: A major contributor to minimal residual disease. Nat. Rev. Cancer. 2009;9:665–674. doi: 10.1038/nrc2714. PubMed DOI

Vasan N., Baselga J., Hyman D.M. A view on drug resistance in cancer. Nature. 2019;575:299–309. doi: 10.1038/s41586-019-1730-1. PubMed DOI PMC

Ramos A., Sadeghi S., Tabatabaeian H. Battling Chemoresistance in Cancer: Root Causes and Strategies to Uproot Them. Int. J. Mol. Sci. 2021;22:9451. doi: 10.3390/ijms22179451. PubMed DOI PMC

Hangauer M.J., Viswanathan V.S., Ryan M.J., Bole D., Eaton J.K., Matov A., Galeas J., Dhruv H.D., Berens M.E., Schreiber S.L., et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature. 2017;551:247–250. doi: 10.1038/nature24297. PubMed DOI PMC

Lim S.Y., Menzies A.M., Rizos H. Mechanisms and strategies to overcome resistance to molecularly targeted therapy for melanoma. Cancer. 2017;123:2118–2129. doi: 10.1002/cncr.30435. PubMed DOI

Sharma P., Hu-Lieskovan S., Wargo J.A., Ribas A. Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy. Cell. 2017;168:707–723. doi: 10.1016/j.cell.2017.01.017. PubMed DOI PMC

Rambow F., Rogiers A., Marin-Bejar O., Aibar S., Femel J., Dewaele M., Karras P., Brown D., Chang Y.H., Debiec-Rychter M., et al. Toward Minimal Residual Disease-Directed Therapy in Melanoma. Cell. 2018;174:843–855.e819. doi: 10.1016/j.cell.2018.06.025. PubMed DOI

Cree I.A., Charlton P. Molecular chess? Hallmarks of anti-cancer drug resistance. BMC Cancer. 2017;17:10. doi: 10.1186/s12885-016-2999-1. PubMed DOI PMC

Candeil L., Gourdier I., Peyron D., Vezzio N., Copois V., Bibeau F., Orsetti B., Scheffer G.L., Ychou M., Khan Q.A., et al. ABCG2 overexpression in colon cancer cells resistant to SN38 and in irinotecan-treated metastases. Int. J. Cancer. 2004;109:848–854. doi: 10.1002/ijc.20032. PubMed DOI

Tada Y., Wada M., Kuroiwa K., Kinugawa N., Harada T., Nagayama J., Nakagawa M., Naito S., Kuwano M. MDR1 gene overexpression and altered degree of methylation at the promoter region in bladder cancer during chemotherapeutic treatment. Clin. Cancer Res. 2000;6:4618–4627. PubMed

Ambudkar S.V., Dey S., Hrycyna C.A., Ramachandra M., Pastan I., Gottesman M.M. Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu. Rev. Pharmacol. Toxicol. 1999;39:361–398. doi: 10.1146/annurev.pharmtox.39.1.361. PubMed DOI

Albermann N., Schmitz-Winnenthal F.H., Z’Graggen K., Volk C., Hoffmann M.M., Haefeli W.E., Weiss J. Expression of the drug transporters MDR1/ABCB1, MRP1/ABCC1, MRP2/ABCC2, BCRP/ABCG2, and PXR in peripheral blood mononuclear cells and their relationship with the expression in intestine and liver. Biochem. Pharmacol. 2005;70:949–958. doi: 10.1016/j.bcp.2005.06.018. PubMed DOI

Alam A., Locher K.P. Structure and Mechanism of Human ABC Transporters. Annu. Rev. Biophys. 2023;52:275–300. doi: 10.1146/annurev-biophys-111622-091232. PubMed DOI

Gottesman M.M., Fojo T., Bates S.E. Multidrug resistance in cancer: Role of ATP-dependent transporters. Nat. Rev. Cancer. 2002;2:48–58. doi: 10.1038/nrc706. PubMed DOI

Fletcher J.I., Haber M., Henderson M.J., Norris M.D. ABC transporters in cancer: More than just drug efflux pumps. Nat. Rev. Cancer. 2010;10:147–156. doi: 10.1038/nrc2789. PubMed DOI

Robey R.W., Pluchino K.M., Hall M.D., Fojo A.T., Bates S.E., Gottesman M.M. Revisiting the role of ABC transporters in multidrug-resistant cancer. Nat. Rev. Cancer. 2018;18:452–464. doi: 10.1038/s41568-018-0005-8. PubMed DOI PMC

Pote M.S., Gacche R.N. ATP-binding cassette efflux transporters and MDR in cancer. Drug Discov. Today. 2023;28:103537. doi: 10.1016/j.drudis.2023.103537. PubMed DOI

Duvivier L., Gerard L., Diaz A., Gillet J.P. Linking ABC transporters to the hallmarks of cancer. Trends Cancer. 2024;10:124–134. doi: 10.1016/j.trecan.2023.09.013. PubMed DOI

Engle K., Kumar G. Cancer multidrug-resistance reversal by ABCB1 inhibition: A recent update. Eur. J. Med. Chem. 2022;239:114542. doi: 10.1016/j.ejmech.2022.114542. PubMed DOI

Dong J., Yuan L., Hu C., Cheng X., Qin J.J. Strategies to overcome cancer multidrug resistance (MDR) through targeting P-glycoprotein (ABCB1): An updated review. Pharmacol. Ther. 2023;249:108488. doi: 10.1016/j.pharmthera.2023.108488. PubMed DOI

Cole S.P. Targeting multidrug resistance protein 1 (MRP1, ABCC1): Past, present, and future. Annu. Rev. Pharmacol. Toxicol. 2014;54:95–117. doi: 10.1146/annurev-pharmtox-011613-135959. PubMed DOI

Hanssen K.M., Haber M., Fletcher J.I. Targeting multidrug resistance-associated protein 1 (MRP1)-expressing cancers: Beyond pharmacological inhibition. Drug Resist. Updates. 2021;59:100795. doi: 10.1016/j.drup.2021.100795. PubMed DOI

Robey R.W., Polgar O., Deeken J., To K.W., Bates S.E. ABCG2: Determining its relevance in clinical drug resistance. Cancer Metastasis Rev. 2007;26:39–57. doi: 10.1007/s10555-007-9042-6. PubMed DOI

Stacy A.E., Jansson P.J., Richardson D.R. Molecular pharmacology of ABCG2 and its role in chemoresistance. Mol. Pharmacol. 2013;84:655–669. doi: 10.1124/mol.113.088609. PubMed DOI

Sarkadi B., Ozvegy-Laczka C., Nemet K., Varadi A. ABCG2—A transporter for all seasons. FEBS Lett. 2004;567:116–120. doi: 10.1016/j.febslet.2004.03.123. PubMed DOI

Kathawala R.J., Espitia C.M., Jones T.M., Islam S., Gupta P., Zhang Y.K., Chen Z.S., Carew J.S., Nawrocki S.T. ABCG2 Overexpression Contributes to Pevonedistat Resistance. Cancers. 2020;12:429. doi: 10.3390/cancers12020429. PubMed DOI PMC

Allain E.P., Rouleau M., Levesque E., Guillemette C. Emerging roles for UDP-glucuronosyltransferases in drug resistance and cancer progression. Br. J. Cancer. 2020;122:1277–1287. doi: 10.1038/s41416-019-0722-0. PubMed DOI PMC

Takano M., Sugiyama T. UGT1A1 polymorphisms in cancer: Impact on irinotecan treatment. Pharmgenomics Pers. Med. 2017;10:61–68. doi: 10.2147/PGPM.S108656. PubMed DOI PMC

Nelson R.S., Seligson N.D., Bottiglieri S., Carballido E., Cueto A.D., Imanirad I., Levine R., Parker A.S., Swain S.M., Tillman E.M., et al. UGT1A1 Guided Cancer Therapy: Review of the Evidence and Considerations for Clinical Implementation. Cancers. 2021;13:1566. doi: 10.3390/cancers13071566. PubMed DOI PMC

Lai J.I., Tseng Y.J., Chen M.H., Huang C.F., Chang P.M. Clinical Perspective of FDA Approved Drugs With P-Glycoprotein Inhibition Activities for Potential Cancer Therapeutics. Front. Oncol. 2020;10:561936. doi: 10.3389/fonc.2020.561936. PubMed DOI PMC

Toyoda Y., Takada T., Suzuki H. Inhibitors of Human ABCG2: From Technical Background to Recent Updates With Clinical Implications. Front. Pharmacol. 2019;10:208. doi: 10.3389/fphar.2019.00208. PubMed DOI PMC

A/S S.O. A Phase 2 Trial of SCO-101 in Combination with FOLFIRI for Patients with Metastatic Colorectal Cancer (mCRC) With Acquired Resistance to FOLFIRI. [(accessed on 10 February 2025)]; Available online: https://clinicaltrials.gov/study/NCT04247256?cond=Cancer&term=sco-101&rank=1.

Helix N., Strobaek D., Dahl B.H., Christophersen P. Inhibition of the endogenous volume-regulated anion channel (VRAC) in HEK293 cells by acidic di-aryl-ureas. J. Membr. Biol. 2003;196:83–94. doi: 10.1007/s00232-003-0627-x. PubMed DOI

Nohr-Nielsen A., Bagger S.O., Brunner N., Stenvang J., Lund T.M. Pharmacodynamic modelling reveals synergistic interaction between docetaxel and SCO-101 in a docetaxel-resistant triple negative breast cancer cell line. Eur. J. Pharm. Sci. 2020;148:105315. doi: 10.1016/j.ejps.2020.105315. PubMed DOI

Bergmann T.K., Stage T.B., Stenvang J., Christophersen P., Jacobsen T.A., Roest N.L., Vestlev P.M., Brunner N. Four phase 1 trials to evaluate the safety and pharmacokinetic profile of single and repeated dosing of SCO-101 in adult male and female volunteers. Basic. Clin. Pharmacol. Toxicol. 2020;127:329–337. doi: 10.1111/bcpt.13466. PubMed DOI PMC

Jensen N.F., Stenvang J., Beck M.K., Hanakova B., Belling K.C., Do K.N., Viuff B., Nygard S.B., Gupta R., Rasmussen M.H., et al. Establishment and characterization of models of chemotherapy resistance in colorectal cancer: Towards a predictive signature of chemoresistance. Mol. Oncol. 2015;9:1169–1185. doi: 10.1016/j.molonc.2015.02.008. PubMed DOI PMC

Wei L.Y., Wu Z.X., Yang Y., Zhao M., Ma X.Y., Li J.S., Yang D.H., Chen Z.S., Fan Y.F. Overexpression of ABCG2 confers resistance to pevonedistat, an NAE inhibitor. Exp. Cell Res. 2020;388:111858. doi: 10.1016/j.yexcr.2020.111858. PubMed DOI

Zander S.A., Kersbergen A., van der Burg E., de Water N., van Tellingen O., Gunnarsdottir S., Jaspers J.E., Pajic M., Nygren A.O., Jonkers J., et al. Sensitivity and acquired resistance of BRCA1;p53-deficient mouse mammary tumors to the topoisomerase I inhibitor topotecan. Cancer Res. 2010;70:1700–1710. doi: 10.1158/0008-5472.CAN-09-3367. PubMed DOI

Sorf A., Sucha S., Morell A., Novotna E., Staud F., Zavrelova A., Visek B., Wsol V., Ceckova M. Targeting Pharmacokinetic Drug Resistance in Acute Myeloid Leukemia Cells with CDK4/6 Inhibitors. Cancers. 2020;12:1596. doi: 10.3390/cancers12061596. PubMed DOI PMC

Sucha S., Sorf A., Svoren M., Vagiannis D., Ahmed F., Visek B., Ceckova M. ABCB1 as a potential beneficial target of midostaurin in acute myeloid leukemia. Biomed. Pharmacother. 2022;150:112962. doi: 10.1016/j.biopha.2022.112962. PubMed DOI

Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022;12:31–46. doi: 10.1158/2159-8290.CD-21-1059. PubMed DOI

Pilotto Heming C., Muriithi W., Wanjiku Macharia L., Niemeyer Filho P., Moura-Neto V., Aran V. P-glycoprotein and cancer: What do we currently know? Heliyon. 2022;8:e11171. doi: 10.1016/j.heliyon.2022.e11171. PubMed DOI PMC

Mo W., Zhang J.T. Human ABCG2: Structure, function, and its role in multidrug resistance. Int. J. Biochem. Mol. Biol. 2012;3:1–27. PubMed PMC

Henrich C.J., Bokesch H.R., Dean M., Bates S.E., Robey R.W., Goncharova E.I., Wilson J.A., McMahon J.B. A high-throughput cell-based assay for inhibitors of ABCG2 activity. J. Biomol. Screen. 2006;11:176–183. doi: 10.1177/1087057105284576. PubMed DOI

Henrich C.J., Robey R.W., Bokesch H.R., Bates S.E., Shukla S., Ambudkar S.V., Dean M., McMahon J.B. New inhibitors of ABCG2 identified by high-throughput screening. Mol. Cancer Ther. 2007;6:3271–3278. doi: 10.1158/1535-7163.MCT-07-0352. PubMed DOI PMC

Le M.T., Hoang V.N., Nguyen D.N., Bui T.H., Phan T.V., Huynh P.N., Tran T.D., Thai K.M. Structure-Based Discovery of ABCG2 Inhibitors: A Homology Protein-Based Pharmacophore Modeling and Molecular Docking Approach. Molecules. 2021;26:3115. doi: 10.3390/molecules26113115. PubMed DOI PMC

Ahmed-Belkacem A., Pozza A., Munoz-Martinez F., Bates S.E., Castanys S., Gamarro F., Di Pietro A., Perez-Victoria J.M. Flavonoid structure-activity studies identify 6-prenylchrysin and tectochrysin as potent and specific inhibitors of breast cancer resistance protein ABCG2. Cancer Res. 2005;65:4852–4860. doi: 10.1158/0008-5472.CAN-04-1817. PubMed DOI

Zhang S., Yang X., Morris M.E. Flavonoids are inhibitors of breast cancer resistance protein (ABCG2)-mediated transport. Mol. Pharmacol. 2004;65:1208–1216. doi: 10.1124/mol.65.5.1208. PubMed DOI

Allen J.D., van Loevezijn A., Lakhai J.M., van der Valk M., van Tellingen O., Reid G., Schellens J.H., Koomen G.J., Schinkel A.H. Potent and specific inhibition of the breast cancer resistance protein multidrug transporter in vitro and in mouse intestine by a novel analogue of fumitremorgin C. Mol. Cancer Ther. 2002;1:417–425. PubMed

Brackman D.J., Giacomini K.M. Reverse Translational Research of ABCG2 (BCRP) in Human Disease and Drug Response. Clin. Pharmacol. Ther. 2018;103:233–242. doi: 10.1002/cpt.903. PubMed DOI PMC

Adamska A., Falasca M. ATP-binding cassette transporters in progression and clinical outcome of pancreatic cancer: What is the way forward? World J. Gastroenterol. 2018;24:3222–3238. doi: 10.3748/wjg.v24.i29.3222. PubMed DOI PMC

Scandion Oncology A/S Scandion Oncology Reports Promising Updated Phase II CORIST Data, Including Topline Overall Survival. [(accessed on 10 February 2025)]. Available online: https://storage.mfn.se/0bae93eb-3725-4176-9faa-2d2197a23dbe/scandion-oncology-reports-promising-updated-corist-phase-ii-data.pdf.

Osborne M.J., Coutinho de Oliveira L., Volpon L., Zahreddine H.A., Borden K.L.B. Overcoming Drug Resistance through the Development of Selective Inhibitors of UDP-Glucuronosyltransferase Enzymes. J. Mol. Biol. 2019;431:258–272. doi: 10.1016/j.jmb.2018.11.007. PubMed DOI PMC

Marques S.C., Ikediobi O.N. The clinical application of UGT1A1 pharmacogenetic testing: Gene-environment interactions. Hum. Genom. 2010;4:238–249. doi: 10.1186/1479-7364-4-4-238. PubMed DOI PMC

Vestlev P.M. Clinical Trial to Investigate Safety, Tolerability and MTD for SCO-101 in Combination with Gemcitabine and Nab-paclitaxel in Inoperable Pancreatic Cancer Patients. (PANTAX-Ib) [(accessed on 10 February 2025)]; Available online: https://clinicaltrials.gov/study/NCT04652206?term=pantax&rank=1.

Scandion Oncology A/S Scandion Oncology Announces Final Data from the CORIST Trial and Is Ready to Move into a Randomized Phase II Proof of Concept Trial in Colorectal Cancer. [(accessed on 13 January 2025)]. Available online: https://scandiononcology.com/mfn_news/scandion-oncology-announces-final-data-from-the-corist-trial-and-is-ready-to-move-into-a-randomized-phase-ii-proof-of-concept-trial-in-colorectal-cancer/

Friesner R.A., Murphy R.B., Repasky M.P., Frye L.L., Greenwood J.R., Halgren T.A., Sanschagrin P.C., Mainz D.T. Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J. Med. Chem. 2006;49:6177–6196. doi: 10.1021/jm051256o. PubMed DOI

Halgren T.A., Murphy R.B., Friesner R.A., Beard H.S., Frye L.L., Pollard W.T., Banks J.L. Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J. Med. Chem. 2004;47:1750–1759. doi: 10.1021/jm030644s. PubMed DOI

Sastry G.M., Adzhigirey M., Day T., Annabhimoju R., Sherman W. Protein and ligand preparation: Parameters, protocols, and influence on virtual screening enrichments. J. Comput. Aided Mol. Des. 2013;27:221–234. doi: 10.1007/s10822-013-9644-8. PubMed DOI

Jackson S.M., Manolaridis I., Kowal J., Zechner M., Taylor N.M.I., Bause M., Bauer S., Bartholomaeus R., Bernhardt G., Koenig B., et al. Structural basis of small-molecule inhibition of human multidrug transporter ABCG2. Nat. Struct. Mol. Biol. 2018;25:333–340. doi: 10.1038/s41594-018-0049-1. PubMed DOI

Jumper J., Evans R., Pritzel A., Green T., Figurnov M., Ronneberger O., Tunyasuvunakool K., Bates R., Zidek A., Potapenko A., et al. Highly accurate protein structure prediction with AlphaFold. Nature. 2021;596:583–589. doi: 10.1038/s41586-021-03819-2. PubMed DOI PMC

Ambjorner S.E.B., Wiese M., Kohler S.C., Svindt J., Lund X.L., Gajhede M., Saaby L., Brodin B., Rump S., Weigt H., et al. The Pyrazolo [3,4-d]pyrimidine Derivative, SCO-201, Reverses Multidrug Resistance Mediated by ABCG2/BCRP. Cells. 2020;9:613. doi: 10.3390/cells9030613. PubMed DOI PMC

Petersen M.J., Lund X.L., Semple S.J., Buirchell B., Franzyk H., Gajhede M., Kongstad K.T., Stenvang J., Staerk D. Reversal of ABCG2/BCRP-Mediated Multidrug Resistance by 5,3′,5′-Trihydroxy-3,6,7,4′-Tetramethoxyflavone Isolated from the Australian Desert Plant Eremophila galeata Chinnock. Biomolecules. 2021;11:1534. doi: 10.3390/biom11101534. PubMed DOI PMC

Bowers K.J., Chow E., Xu H., Dror R.O., Eastwood M.P., Gregersen B.A., Klepeis J.L., Kolossvary I., Moraes M.A., Sacerdoti F.D., et al. Scalable Algorithms for Molecular Dynamics Simulations on Commodity Clusters; Proceedings of the 2006 ACM/IEEE Conference on Supercomputing (SC06); Tampa, FL, USA. 11–17 November 2006; New York, NY, USA: IEEE; 2007.