Tasigna® (AMN107, Nilotinib) is a recently approved BCR-ABL kinase inhibitor for the treatment of drug-resistant chronic myelogenous leukemia (CML). The efflux of tyrosine kinase inhibitors by ATP-binding cassette (ABC) drug transporters, which actively extrude the drugs out of the cells by utilizing ATP as energy source, has been linked to the development of drug resistance in CML patients. In collaboration with the Ambudkar lab (NCI), we designed and characterized a fluorescent derivative of Tasigna to study its interaction with two major ABC transporters, P-glycoprotein (Pgp) and ABCG2, in in vitro and ex vivo assays. The BODIPY® FL Tasigna inhibited the BCR-ABL kinase activity in K562 cells and was also effluxed by Pgp- and ABCG2-expressing cells in both cultured cells and rat brain capillaries expressing Pgp and ABCG2. Further, we propose that BODIPY® FL Tasigna can potentially be used as an in vivo probe to study Tasigna in imaging Pgp and/or ABCG2 expressing cancer cells and other preclinical studies. A similar approach may be used to study whether a given TKI is transported by Pgp or ABCG2. It could also be adapted for use in in vivo imaging studies to assess the accumulation of xenobiotics in the brain that are transported by Pgp or ABCG2.
National Cancer Institute
Suresh Ambudkar, Ph.D.
Public Health Impact
This study describes a fluorescent conjugate of the drug Tasigna and utilizes this novel agent to demonstrate that this drug is transported by Pgp and ABCG2.
Shukla S, Skoumbourdis AP, Walsh MJ, et al. Synthesis and characterization of a BODIPY conjugate of the BCR-ABL kinase inhibitor Tasigna (nilotinib): evidence for transport of Tasigna and its fluorescent derivative by ABC drug transporters. Mol Pharm, 2011;8(4):1292-1302.
The BCR-ABL inhibitor Tasigna is a substrate for drug transporters.