Tariquidar-related triazoles as potent, selective and stable inhibitors of ABCG2 (BCRP)

Structural basis of drug recognition by the multidrug transporter ABCG2

“…If the classification of compounds into inhibitors or substrates is a continuum, tariquidar is an example of a compound around the middle of this continuum. This molecular interpretation could be useful in guiding the design of larger inhibitors that do not adopt a C-shape like tariquidar but maintain a set of interactions with residues on the TM1b helices as observed in tariquidar derivatives[41].…”

Scaffold fragmentation and substructure hopping reveal potential, robustness, and limits of computer-aided pattern analysis (C@PA)

“…3 Visualization of the classification of modulators of ABCB1, ABCC1, and ABCG2 as proposed earlier [15] : ‘class 7 compounds’ are defined as triple ABCB1, ABCC1, and ABCG2 inhibitors that exert their half-maximal effect against these transporters below 10 µM. This has up to date been reported for 56 compounds [15] , [43] , [45] , [62] , [67] , [75] , [93] , [94] , [95] , [98] , [99] , [101] , [103] , [107] , [109] , [110] , [111] , [112] , [113] , [118] , [119] , [120] , [121] , [122] , [123] , [126] . Amongst these molecules are the compounds revealed by C@PA, 8–9 and 11 .…”

“…3 ). Besides the above mentioned 56 class 7 compounds [15] , [43] , [45] , [62] , [67] , [75] , [93] , [94] , [95] , [98] , [99] , [101] , [103] , [107] , [109] , [110] , [111] , [112] , [113] , [118] , [119] , [120] , [121] , [122] , [123] , [126] , further 20 compounds are known which exert their inhibitor effect against ABCB1, ABCC1, and/or ABCG2 up to 15.0 µM [15] , [45] , [75] , [93] , [98] , [101] , [102] , [110] , [113] , [116] , [117] , [119] . Considering this, compound 23 belongs to the 76 most potent multitarget ABCB1, ABCC1, and ABCG2 inhibitors known until today.…”

“…Several defined extended positive hits were reflected in the discovered multitarget ABCB1, ABCC1, and ABCG2 inhibitors 16 and 22 – 24 , namely (i) pyrimidine ( 24 ), (ii) pyridine ( 22–24 ), (iii) isoxazole ( 16 ), (iv) imidazole ( 23 ), (v) pyrazole ( 22 and 24 ), and pyrrolidine ( 16 ). This discovery ultimately showed that the 8 clear positive hits as derived from C@PA [15] may indeed be supported by secondary positive hits, revealing the high potential of substructure extension in C@PA. A detailed analysis of these substructures according to their statistical distribution amongst the 133 known multitarget ABCB1, ABCC1, and ABCG2 inhibitors [15] , [43] , [45] , [62] , [67] , [75] , [93] , [94] , [95] , [96] , [97] , [98] , [99] , [100] , [101] , [102] , [103] , [104] , [105] , [106] , [107] , [108] , [109] , [110] , [111] , [112] , [113] , [114] , [115] , [116] , [117] , [118] , [119] , [120] , [121] , [122] , [123] , [124] , [125] , [126] showed that the substructures isoxazole, imidazole, pyrazole, and pyrrolidine occurred only 1, 3, 1, and 2 times [67] , [96] , [106] , [107] , [117] , [127] , respectively, in these 133 compounds, and were generally only present in 1, 16, 8, and 8 molecules, respectively, of the initial dataset of 1,049 compounds as used in C@PA [15] . Our results indicate that these ‘under-represented substructures’ pose a high exploratory potential for the i...…”

“…As indicated above, ABCB1, ABCC1, and ABCG2 are the most investigated and understood ABC transporters, and hence, represent model targets for the generation of pan-ABC transporter inhibitors [15] . However, even for these well-studied ABC transporters, only 133 broad-spectrum ABCB1, ABCC1, and ABCG2 inhibitors were described to date [15] , [43] , [45] , [62] , [67] , [75] , [93] , [94] , [95] , [96] , [97] , [98] , [99] , [100] , [101] , [102] , [103] , [104] , [105] , [106] , [107] , [108] , [109] , [110] , [111] , [112] , [113] , [114] , [115] , [116] , [117] , [118] , [119] , [120] , [121] , [122] , [123] , [124] , [125] , [126] , amongst which only 56 exerted their effects below 10 µM [15] , [43] , [45] , [62] , [67] , [75] , [93] , [94] , [95] , [98] , [99] , [101] , [103] , [107] , [109] , [110] , [111] , [112] , [113] , [118] , [119] , [120] , [121] ,…”