Identification of novel specific and general inhibitors of the three major human ATP-binding cassette transporters P-gp, BCRP and MRP2 among registered drugs.
OBJECTIVE
To study the inhibition patterns of the three major human ABC transporters P-gp (ABCB1), BCRP (ABCG2) and MRP2 (ABCC2), using a dataset of 122 structurally diverse drugs.


METHODS
Inhibition was investigated in cellular and vesicular systems over-expressing single transporters. Computational models discriminating either single or general inhibitors from non-inhibitors were developed using multivariate statistics.


RESULTS
Specific (n = 23) and overlapping (n = 19) inhibitors of the three ABC transporters were identified. GF120918 and Ko143 were verified to specifically inhibit P-gp/BCRP and BCRP in defined concentration intervals, whereas the MRP inhibitor MK571 was revealed to inhibit all three transporters within one log unit of concentration. Virtual docking experiments showed that MK571 binds to the ATP catalytic site, which could contribute to its multi-specific inhibition profile. A computational model predicting general ABC inhibition correctly classified 80% of both ABC transporter inhibitors and non-inhibitors in an external test set.


CONCLUSIONS
The inhibitor specificities of P-gp, BCRP and MRP2 were shown to be highly overlapping. General ABC inhibitors were more lipophilic and aromatic than specific inhibitors and non-inhibitors. The identified specific inhibitors can be used to delineate transport processes in complex experimental systems, whereas the multi-specific inhibitors are useful in primary ABC transporter screening in drug discovery settings.
Pharmaceutical Screening and Informatics, Department of Pharmacy, Uppsala University, P.O. Box 580, 751 23, Uppsala, Sweden.
Pär
P
Matsson
Jenny M
JM
Pedersen
Ulf
U
Norinder
Christel A S
CA
Bergström
Per
P
Artursson
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000166:Acridines / Q000494:pharmacology; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D002460:Cell Line; D003198:Computer Simulation; D054659:Diketopiperazines; D006576:Heterocyclic Compounds, 4 or More Rings; D006801:Humans; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D044005:Tetrahydroisoquinolines / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000166:Acridines; D000241:Adenosine; D000255:Adenosine Triphosphate; D054659:Diketopiperazines; D006576:Heterocyclic Compounds, 4 or More Rings; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D011422:Propionates; D011804:Quinolines; D044005:Tetrahydroisoquinolines; C541506:3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino(1',2'-1,6)pyrido(3,4-b)indol-3-yl)propionic acid tert-butyl ester; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; C059141:verlukast; C083501:Elacridar