Discovering Novel Modulators and Effective Drug Combination Therapy against Transporter-Mediated Multidrug Resistant Cancers

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

Project Details

Abstract

A major cause of death in cancer is due to metastatic cancers that are resistant to conventional chemotherapy. Multidrug resistance (MDR) caused by the overexpression of ATP-Binding Cassette (ABC) transporters ABCB1 and ABCG2 is one of the major obstacle in chemotherapy. Collectively, these two transporters confer resistance, limit the oral bioavailability, distribution and penetration of most conventional anticancer agents, as well as many newly developed targeted drugs, hence hampers the overall effectiveness of chemotherapeutic agents. As for now, it is agreed that direct modulation of ABC transporters would be the cheapest and most effective way to overcome transporter-mediated MDR. Unfortunately, due to the lack of structural information on the substrate-binding site(s) of ABCB1 and ABCG2, the progress on the computer-aided drug screening and structure-based drug design have been slow and ineffective. Therefore, we intend to utilize a fluorescent cell-based high-throughput drug screening system we have developed, to rapidly identify compounds and purified natural products from inhibitor libraries and natural product libraries that can attenuate the function or expression of human ABCB1 and/or ABCG2.While the data obtained from inhibitor libraries will provide us with substantial structure-activity information, the data from natural product libraries will provide valuable information on much greater chemical diversity. Thereafter, we will carefully examined all positive hits through a series of biochemical and pharmacological characterization, as well as in vivo determinations to ensure the lead compounds can sufficiently restore drug sensitivity in MDR cancers in vitro and in vivo, and suitable for further development into clinically active chemosensitizers.

Project IDs

Project ID:PC10408-2386
External Project ID:MOST104-2320-B182-039
StatusFinished
Effective start/end date01/08/1531/07/16

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