[Show abstract][Hide abstract] ABSTRACT: ABCG2 is responsible for the multidrug resistance (MDR) phenotype, and strongly modulates cancer outcomes. Its high expression at a number of physiological barriers, including blood-brain and intestinal barriers, impacts on drug pharmacokinetics parameters. We characterized MBL-II-141, a specific and potent ABCG2 inhibitor. Combination of 10 mg/kg MBL-II-141 with the anticancer agent CPT-11 completely blocked the growth of 90% freshly implanted ABCG2-positive tumors. Moreover, the same combination slowed the growth of already established tumors. As required for preclinical development, we defined the main pharmacokinetics parameters of MBL-II-141 and its influence on the kinetics of CPT-11 and its active metabolite SN-38 in mice. MBL-II-141 distribution into the brain occurred at a low, but detectable, level. Interestingly, preliminary data suggested that MBL-II-141 is well tolerated (at 50 mg/kg) and absorbed upon force-feeding. MBL-II-141 induced a potent sensitization of ABCG2-positive xenografts to CPT-11 through in vivo ABCG2 inhibition. MBL-II-141 strongly increased CPT-11 levels in the brain, and therefore would be a valuable agent to improve drug distribution into the brain to efficiently treat aggressive gliomas. Safety and other pharmacological data strongly support the reglementary preclinical development of MBL-II-141.
[Show abstract][Hide abstract] ABSTRACT: We recently identified a chromone derivative, 5-(4-bromobenzyloxy)-2-(2-(5-methoxyindolyl)ethyl-1-carbonyl)-4H-chromen-4-one, named here chromone 1, as a potent, selective, non-toxic and non-transported inhibitor of ABCG2-mediated drug efflux (Valdameri et al. J. Med. Chem. 2012, 55, 966). We now synthesized a series of 14 derivatives to study structure-activity relationships controlling both drug efflux and ATPase activity of ABCG2, and to elucidate their molecular mechanism of interaction and inhibition. It was found that the 4-bromobenzyloxy substituent at position 5 and the methoxyindole are important for both inhibition of mitoxantrone efflux and inhibition of basal ATPase activity. Quite interestingly, methylation of the central amide nitrogen strongly altered the high-affinity and complete inhibition of mitoxantrone efflux, as well as the inhibition of coupled ATPase activity. These results allowed the identification of a critical central inhibitory moiety of chromones that has never been investigated previously, in any series of inhibitors.
[Show abstract][Hide abstract] ABSTRACT: ABCG2 impacts oral availability, tissue distribution and excretion of its substrates, including anticancer and anti-infectious drugs. Highly expressed at physiological barriers, its secretion level significantly controls drug distribution. Furthermore, its increased content into many types of cancer may lead to cell chemoresistance. Owing to the clinical relevance of ABCG2 in the multidrug resistance phenomenon, ABCG2 constitutes an appealing therapeutic target to increase drug distribution. Development of ABCG2 inhibitors can be used in combination with anticancer drugs to block the drug secretion from cancer cells. Very recently, an alternative use of ABCG2 inhibitors in enhancing the bioavailability of ABCG2 substrates has emerged. Hence, it is important to investigate ABCG2 inhibitors with high selectivity, high potency and safety. New inhibitors discovered during the last 5 years will be presented and discussed.
[Show abstract][Hide abstract] ABSTRACT: Easy as A B C! 6-Halochromone derivatives bearing a tryptamine moiety were evaluated as inhibitors of the breast cancer resistance protein (BCRP)/ABCG2. The 6-bromo analogue has been identified as a highly potent, selective and nontoxic inhibitor of BCRP. The facile synthesis from commercial starting materials makes this inhibitor an ideal candidate for preclinical investigations.
[Show abstract][Hide abstract] ABSTRACT: A series of 13 disubstituted chromones was synthesized. Two types of substituents, on each side of the scaffold, contributed to both the potency of ABCG2 inhibition and the cytotoxicity. The best compound, 5-(4-bromobenzyloxy)-2-(2-(5-methoxyindolyl)ethyl-1-carbonyl)-4H-chromen-4-one (6g), displayed high-affinity inhibition and low cytotoxicity, giving a markedly high therapeutic index. The chromone derivative specifically inhibited ABCG2 versus other multidrug ABC transporters and was not transported. It constitutes a highly promising candidate for in vivo chemosensitization of ABCG2-expressing tumors.