Identification of Thienopyrimidine Scaffold as an Inhibitor of the ABC Transport Protein ABCC1 (MRP1) and Related Transporters Using a Combined Virtual Screening Approach

Journal of Medicinal Chemistry
2019.0

Abstract

A virtual screening protocol with combination of similarity search and pharmacophore modeling was applied to virtually screen a large compound library to gain new scaffolds regarding ABCC1 inhibition. Biological investigation of promising candidates revealed four compounds as ABCC1 inhibitors, three of them with scaffolds not associated with ABCC1 inhibition until now. The best hit molecule-a thienopyrimidine-was a moderately potent, competitive inhibitor of the ABCC1-mediated transport of calcein AM which also sensitized ABCC1-overexpressing cells toward daunorubicin. Further evaluation showed that it was a moderately potent, competitive inhibitor of the ABCB1-mediated transport of calcein AM, and noncompetitive inhibitor of the ABCG2-mediated pheophorbide A transport. In addition, the thienopyrimidine could also sensitize ABCB1- as well as ABCG2-overexpressing cells toward daunorubicin and SN-38, respectively, in concentration ranges that qualified it as one of the ten best triple ABCC1/ABCB1/ABCG2 inhibitors in the literature. Besides, three more new multitarget inhibitors were identified by this virtual screening approach.

Knowledge Graph

Similar Paper

Identification of Thienopyrimidine Scaffold as an Inhibitor of the ABC Transport Protein ABCC1 (MRP1) and Related Transporters Using a Combined Virtual Screening Approach
Journal of Medicinal Chemistry 2019.0
Superior Pyrimidine Derivatives as Selective ABCG2 Inhibitors and Broad-Spectrum ABCB1, ABCC1, and ABCG2 Antagonists
Journal of Medicinal Chemistry 2020.0
9-Deazapurines as Broad-Spectrum Inhibitors of the ABC Transport Proteins P-Glycoprotein, Multidrug Resistance-Associated Protein 1, and Breast Cancer Resistance Protein
Journal of Medicinal Chemistry 2017.0
Pyrimidine: A promising scaffold for optimization to develop the inhibitors of ABC transporters
European Journal of Medicinal Chemistry 2020.0
2-Indolylmethylenebenzofuranones as first effective inhibitors of ABCC2
European Journal of Medicinal Chemistry 2016.0
Thieno[2,3-b]pyridines—A new class of multidrug resistance (MDR) modulators
Bioorganic & Medicinal Chemistry 2014.0
Rational drug design of 6-substituted 4-anilino-2-phenylpyrimidines for exploration of novel ABCG2 binding site
European Journal of Medicinal Chemistry 2021.0
Indolyl-pyrrolone as a new scaffold for Pim1 inhibitors
Bioorganic & Medicinal Chemistry Letters 2009.0
Synthesis and Biological Evaluation of 4-Anilino-quinazolines and -quinolines as Inhibitors of Breast Cancer Resistance Protein (ABCG2)
Journal of Medicinal Chemistry 2016.0
Discovery of Novel Flavonoid Dimers To Reverse Multidrug Resistance Protein 1 (MRP1, ABCC1) Mediated Drug Resistance in Cancers Using a High Throughput Platform with “Click Chemistry”
Journal of Medicinal Chemistry 2018.0