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1. Mol Cancer Ther. 2012 May 16. [Epub ahead of print]

New Use for an Old Drug: Inhibiting ABCG2 with Sorafenib.

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

1Molecular Immunology, Institute of Basic Medical Sciences.

Human ABCG2, a member of the ATP-binding cassette transporter superfamily,
represents a promising target for sensitizing multidrug resistance in cancer
chemotherapy. Although lots of ABCG2 inhibitors were identified, none of them has
been tested clinically maybe due to 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 showing closer similarity to
degradation-induced mechanism of action. Based on 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 report that sorafenib may be a good candidate for chemo-sensitizing
agent targeting ABCG2-mediated multidrug resistance. The present study may
facilitate the rediscovery of new functions of structurally diverse old drugs and
provide a more effective and safe way of sensitizing multidrug resistance in
cancer chemotherapy.

PMID: 22593228 [PubMed - as supplied by publisher]