Strategies for targeting the multidrug resistance-1 (MDR1)/P-gp transporter in human malignancies.
ATP-binding cassette (ABC) transporters are a super family of channel proteins that include multi-drug resistance 1 (MDR1/P-gp) and multi-drug resistance related proteins (MRPs) whose functions include the efflux of ions, nutrients, lipids, amino acids, peptides, proteins and drugs. The three-dimensional structures of bacterial and human ABC transporters demonstrate that these proteins are ATP-dependent molecular machines that scan the inner membrane leaflet for lipids/drugs and flip them to the outer membrane leaflet. In many human cancers, the level of expression of MDR1 is an important independent prognostic factor that determines response to combination chemotherapy. Intrinsic and acquired resistance to chemotherapy exposure are due to a high level of MDR1 expression that enhances drug efflux, with associated poor clinical outcome and lower complete remission (CR) rates. Recent clinical trials in hematological and solid malignancies have shown promise for a prolonged remission and improved overall survival when the MDR1 P-gp is inhibited when combined with chemotherapy. Structure-based homology modeling of these ABC transporters may help design novel drug candidates to both the membrane-spanning domain (MSD) and the nucleotide-binding domain (NBD) located within the cytoplasm. This review will highlight advances in the utilization of homology modeling in the drug discovery process and how this will impact on fundamental insights to the development of novel therapeutics that could alter and/or inhibit their functions.
Mahadevan
Daruka
D
University of Arizona Cancer Center, Tucson, AZ 85724, USA. dmahadevan @azcc.arizona.edu
Shirahatti
Nikhil
N
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004357:Drug Synergism; D006801:Humans; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents