Medicinal chemistry and chemical biology of new generation taxane antitumor agents.
P-glycoprotein (P-GP)-based multidrug resistance (MDR) and undesirable side effects are significant drawbacks to the clinical use of paclitaxel and docetaxel. Extensive SAR studies of taxanes in these laboratories led to the discovery of new generation taxanes that are highly active against not only drug-sensitive but also drug-resistant human cancer cell lines as well as tumor xenografts in mice. One of these second generation taxanes, SB-T-110131 (IDN5109), exhibited excellent pharmacological profile in the preclinical studies and has been selected for clinical development (recoded as Bay 59-8862), which is currently in the phase II clinical trials. Bay 59-8862 is orally active with high bioavailability, showing excellent activity against a variety of drug-resistant tumors. "Advanced second generation taxanes" show essentially no difference in cytotoxicity against drug-resistant and drug-sensitive cell lines, virtually overcoming MDR. Photoaffinity labeling of P-GP using photoreactive radiolabeled paclitaxel analogs has disclosed the paclitaxel-binding domain of P-GP. Highly efficient taxane-based MDR reversal agents (TRAs) have also been developed, which can recover the cytotoxicity of paclitaxel to practically the original level against paclitaxel-resistant MDR expressing cancer cells. Highly promising results have emerged from the study of taxane-monoclonal antibody (MAb) immunoconjugates, which have been proved to specifically deliver extremely cytotoxic agents to tumor in an animal model.
Ojima
Iwao
I
Chemistry Department, State University of New York at Stony Brook, 11794-3400, USA. iojima@notes.cc.sunysb.edu
Geney
Raphael
R
Ungureanu
Ioana Maria
IM
Li
Dansu
D
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D001952:Bridged-Ring Compounds / Q000737:chemistry / Q000494:pharmacology*; D002986:Clinical Trials as Topic; D018432:Drug Resistance, Multiple; D006801:Humans; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D043823:Taxoids
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D043823:Taxoids; C080625:taxane; C404743:IDN 5109; D017239:Paclitaxel