New use for an old drug: inhibiting ABCG2 with sorafenib.

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Wei Y, Ma Y, Zhao Q, Ren Z, Li Y, Hou T, Peng H

New use for an old drug: inhibiting ABCG2 with sorafenib.

Mol Cancer Ther. 2012 Aug;11(8):1693-702. doi: 10.1158/1535-7163.MCT-12-0215. Epub 2012 May 16.

PubMed ID

22593228 [ View in PubMed

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Abstract

Human ABCG2, a member of the ATP-binding cassette transporter superfamily, represents a promising target for sensitizing MDR in cancer chemotherapy. Although lots of ABCG2 inhibitors were identified, none of them has been tested clinically, maybe because of several problems such as toxicity or safety and pharmacokinetic uncertainty of compounds with 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 inducing ABCG2 degradation in lysosome in addition to inhibiting its function. Previously, we reported some novel dual-acting ABCG2 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.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Sorafenib	Broad substrate specificity ATP-binding cassette transporter ABCG2	Protein	Humans	Unknown	Substrate Inhibitor	Details