Therapeutic Discovery New Use for an Old Drug : Inhibiting ABCG 2 with Sorafenib
semanticscholar(2012)
Abstract
Human ABCG2, a member of the ATP-binding cassette transporter superfamily, represents a promising target for sensitizingMDR in cancer chemotherapy.Although lots ofABCG2 inhibitorswere identified, none of them has been tested clinically, maybe because of several problems such as toxicity or safety and pharmacokinetic uncertainty of compoundswith novel chemical structures. One efficient solution is to rediscover new uses for existing drugs with known pharmacokinetics and safety profiles. Here, we found the new use for sorafenib,which has a dual-mode action by inducingABCG2degradation in lysosome in addition to inhibiting its function. Previously,we reported somenovel dual-actingABCG2 inhibitors that showed closer similarity to degradation-induced mechanism of action. On the basis of these ABCG2 inhibitors with diverse chemical structures, we developed a pharmacophore model for identifying the critical pharmacophore features necessary for dual-acting ABCG2 inhibitors. Sorafenib forms impressive alignment with the pharmacophore hypothesis, supporting the argument that sorafenib is a potential ABCG2 inhibitor. This is the first article that sorafenib may be a good candidate for chemosensitizing agent targeting ABCG2-mediated MDR. This study may facilitate the rediscovery of new functions of structurally diverse old drugs and provide a more effective and safe way of sensitizing MDR in cancer chemotherapy. Mol Cancer Ther; 11(8); 1693–702. 2012 AACR.
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