Vesicular ATP-binding cassette transporters in human disease: relevant aspects of their organization for future drug development

Abstract

‡ Authors contributed equally " besides ABC transporters themselves, the vesicles in which they reside, the lipid raft microdomains in which they are organized and oligomerized as well as the cytoskeleton are new potential drug targets. "

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

“…This suggests that compound 23 represents a good lead molecule for further improvement via synthesis to gain novel potent multitarget ABCB1, ABCC1, and ABCG2 inhibitors focusing ABCC1 inhibition. Furthermore, the findings support the hypothesis of a common multitarget binding site amongst different ABC transporter subfamilies as postulated earlier [15] , [74] .

Fig.

…”

“…Furthermore, recent advances in crystallographic methodologies, such as cryo-EM, increasingly provided structural information of ABC transporters of different sub-families. This will allow for the analysis of the ‘multitarget binding site’ [15] , [74] with the identified multitarget pan-ABC transporter inhibitors applying a combination of structure-based computational approaches. Using the knowledge derived from C@PA, C@PA_1.2, and potentially C@PA_1.X, new truly multitarget pan-ABC transporter modulators will be derived that could address less- and under-studied ABC transporters to tackle common and rare human diseases.…”

“…However, these approaches always took only one transporter into account, completely leaving out the potential of multitarget inhibition. Multitargeting is a promising approach to explore under-studied ABC transporters by targeting similar or mutually overlapping binding sites [15] , [73] , [74] . Several pharmacological drugs have already been revealed as (weak) pan-ABC transporter inhibitors (=inhibiting several ABC transporters simultaneously), as for example, benzbromarone ( 1 ; ABCB1 [75] , ABCB11 [20] , ABCC1-6 [23] , [24] , [58] , [76] , [77] , and ABCG2 [75] ), cyclosporine A ( 2 ; ABCA1 [27] , ABCB1 [16] , ABCB4 [78] , ABCB11 [20] , ABCC1–2 [23] , [58] , ABCC10 [24] , ABCG1–2 [75] , [79] ), glibenclamide (glyburide, 3 ; ABCA1 [29] , ABCB11 [20] , ABCC1 [23] , ABCC5 [80] , ABCC7–9 [81] , [82] , [83] , ABCG2 [58] ), probenecid ( 4 ; ABCA8 [84] , ABCC1–6 [23] , [24] , [85] , [86] , [87] , ABCC10 [88] ), verapamil ( 5 ; ABCA8 [84] , ABCB1 [16] , ABCB4–5 [54] , [78] , ABCB11 [89] , ABCC1 [23] , ABCC4 [90] , ABCC10 [88] , ABCG2 [58] ), or verlukast (MK571, 6 ; ABCA8 [84] , ABCB4 [78] , ABCB11 [20] , ABCC1–5 [23] , [58] , [80] , [87] , [91] , ABCC10–11 [24] , [92] , ABCG2 [58] ).…”

C@PA: Computer-Aided Pattern Analysis to Predict Multitarget ABC Transporter Inhibitors

“… 5 − 7 Two concluding postulations emerged very recently: (i) ABC transporters have a differing (individual) substrate range, which increases cross-resistance in case of their co-expression. 6 , 8 These individual substrate ranges combined cover almost the whole range of today’s applied antineoplastic agents; 5 − 8 (ii) ABC transporters have also an overlapping (collective) substrate range, enabling them to compensate for the selective inhibition and/or downregulation of their functional counterpart(s). These collective substrate ranges account for a regulatory dependency of ABC transporter expression in terms of a triggered upregulation.…”

Strategies to gain novel Alzheimer’s disease diagnostics and therapeutics using modulators of ABCA transporters

“… 1 - 4 They play a major role in determining the distribution of intrinsic and xenobiotic drugs between intra- and intercellular compartments. 5 , 6 The clinical relevance of ABC transporters became pronounced when their expression was correlated to cross-resistance of cancer cells to antineoplastic agents. 3 , 7 - 13 This phenomenon is called ‘multidrug resistance’ (MDR).…”