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Start Over Author "Jabor Gozzi G" Topic atp-binding cassette transporters
2 results on '"Jabor Gozzi G"'

1. The linker region of breast cancer resistance protein ABCG2 is critical for coupling of ATP-dependent drug transport.

Author

Macalou S, Robey RW, Jabor Gozzi G, Shukla S, Grosjean I, Hegedus T, Ambudkar SV, Bates SE, and Di Pietro A

Subjects
ATP Binding Cassette Transporter, Subfamily G, Member 2, ATP-Binding Cassette Transporters chemistry, ATP-Binding Cassette Transporters genetics, Adenosine analogs & derivatives, Adenosine pharmacology, Adenosine Triphosphatases antagonists & inhibitors, Adenosine Triphosphatases metabolism, Adenosine Triphosphate metabolism, Amino Acid Sequence, Antineoplastic Agents pharmacology, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cell Proliferation drug effects, Cell Survival drug effects, Diketopiperazines, Drug Resistance, Neoplasm, Female, HEK293 Cells, Heterocyclic Compounds, 4 or More Rings, Humans, Mitoxantrone metabolism, Molecular Sequence Data, Mutagenesis, Site-Directed, Neoplasm Proteins chemistry, Neoplasm Proteins genetics, Sequence Alignment, ATP-Binding Cassette Transporters metabolism, Antineoplastic Agents metabolism, Neoplasm Proteins metabolism
Abstract

The ATP-binding cassette (ABC) transporters of class G display a different domain organisation than P-glycoprotein/ABCB1 and bacterial homologues with a nucleotide-binding domain preceding the transmembrane domain. The linker region connecting these domains is unique and its function and structure cannot be predicted. Sequence analysis revealed that the human ABCG2 linker contains a LSGGE sequence, homologous to the canonical C-motif/ABC signature present in all ABC nucleotide-binding domains. Predictions of disorder and of secondary structures indicated that this C2-sequence was highly mobile and located between an α-helix and a loop similarly to the C-motif. Point mutations of the two first residues of the C2-sequence fully abolished the transport-coupled ATPase activity, and led to the complete loss of cell resistance to mitoxantrone. The interaction with potent, selective and non-competitive, ABCG2 inhibitors was also significantly altered upon mutation. These results suggest an important mechanistic role for the C2-sequence of the ABCG2 linker region in ATP binding and/or hydrolysis coupled to drug efflux.

Published
2016
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2. Converting potent indeno[1,2-b]indole inhibitors of protein kinase CK2 into selective inhibitors of the breast cancer resistance protein ABCG2.

Author

Jabor Gozzi G, Bouaziz Z, Winter E, Daflon-Yunes N, Aichele D, Nacereddine A, Marminon C, Valdameri G, Zeinyeh W, Bollacke A, Guillon J, Lacoudre A, Pinaud N, Cadena SM, Jose J, Le Borgne M, and Di Pietro A

Subjects
ATP Binding Cassette Transporter, Subfamily G, Member 2, ATP-Binding Cassette Transporters metabolism, Biological Transport drug effects, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Breast Neoplasms pathology, Casein Kinase II metabolism, Cell Proliferation drug effects, Cell Survival drug effects, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm drug effects, Female, HEK293 Cells, Humans, Indoles chemical synthesis, Indoles chemistry, MCF-7 Cells, Mitoxantrone metabolism, Models, Chemical, Molecular Structure, Neoplasm Proteins metabolism, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, ATP-Binding Cassette Transporters antagonists & inhibitors, Casein Kinase II antagonists & inhibitors, Indoles pharmacology, Neoplasm Proteins antagonists & inhibitors, Protein Kinase Inhibitors pharmacology
Abstract

A series of indeno[1,2-b]indole-9,10-dione derivatives were synthesized as human casein kinase II (CK2) inhibitors. The most potent inhibitors contained a N(5)-isopropyl substituent on the C-ring. The same series of compounds was found to also inhibit the breast cancer resistance protein ABCG2 but with totally different structure-activity relationships: a N(5)-phenethyl substituent was critical, and additional hydrophobic substituents at position 7 or 8 of the D-ring or a methoxy at phenethyl position ortho or meta also contributed to inhibition. The best ABCG2 inhibitors, such as 4c, 4h, 4i, 4j, and 4k, behaved as very weak inhibitors of CK2, whereas the most potent CK2 inhibitors, such as 4a, 4p, and 4e, displayed limited interaction with ABCG2. It was therefore possible to convert, through suitable substitutions of the indeno[1,2-b]indole-9,10-dione scaffold, potent CK2 inhibitors into selective ABCG2 inhibitors and vice versa. In addition, some of the best ABCG2 inhibitors, which displayed a very low cytotoxicity, thus giving a high therapeutic ratio, and appeared not to be transported, constitute promising candidates for further investigations.

Published
2015
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