The 2-aminopyrimidine ring as a new scaffold for potent MRP1 inhibitors

  • Eur J Med Chem. 2026 Jan 15;302(Pt 3):118364. doi: 10.1016/j.ejmech.2025.118364.
Marijo Čičak  1 ,  Jaroslav Kozák  2 ,  Miroslav Hájek  2 ,  Pavel Kraina  2 ,  Viktor Kolman  2 ,  Alžbeta Magdolenová  2 ,  Jitka Viktorová  3 ,  Helena Mertlíková-Kaiserová  4 ,  Zlatko Janeba  5
Affiliations
  • 1. Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences, Flemingovo nám. 2, 16610, Prague, Czech Republic; University of Chemistry and Technology, Technická 5, 166 28, Prague, Czech Republic.
  • 2. Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences, Flemingovo nám. 2, 16610, Prague, Czech Republic.
  • 3. University of Chemistry and Technology, Technická 5, 166 28, Prague, Czech Republic.
  • 4. Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences, Flemingovo nám. 2, 16610, Prague, Czech Republic. Electronic address: [email protected].
  • 5. Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences, Flemingovo nám. 2, 16610, Prague, Czech Republic. Electronic address: [email protected].
PMID: 41275662 DOI: 10.1016/j.ejmech.2025.118364
Abstract

Multidrug resistance-associated protein 1 (MRP1) is a key ATP-binding cassette (ABCC1) transporter involved in the efflux of a wide range of substrates, including endogenous molecules and therapeutic drugs. Overexpression of MRP1 in certain cancers plays a significant role in the development of multidrug resistance (MDR), leading to reduced efficacy of chemotherapeutic agents. MRP1 inhibition offers a promising strategy to improve the therapeutic potential of standard-of-care chemotherapy in Tumors exhibiting MDR phenotype. In this study, a series of novel polysubstituted 2-aminopyrimidine derivatives have been designed and synthesized to inhibit MRP1 transporter, guided by structure-activity relationship (SAR) studies based on a library of polysubstituted pyrimidines (423 compounds). Among the newly synthesized compounds, six out of eight 4,5,6-trisubstituted 2-aminopyrimidines demonstrated strong inhibition of calcein-AM efflux from MRP1-overexpressing doxorubicin (DOX)-resistant Glioblastoma U87MG cells. Simultaneously, they sensitized the cells to the cytotoxic effect of DOX in a dose-dependent manner. Compound 21 (EC50 = 177 nM) proved to be fivefold more potent than the reference MRP1/P-gp inhibitor Reversan in calcein accumulation assay and completely abolished DOX resistance at submicromolar concentrations. Thus, 4,5,6-trisubstituted 2-aminopyrimidines represent a promising class of MRP1 inhibitors that could be used as Adjuvant therapy to overcome MDR in combination Cancer therapy.

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