Zosuquidar Trihydrochloride

Fluoroquinolone tissue distribution and cellular accumulation are hindered by efflux transporters, including ATP-binding cassette subfamily B member 1 (ABCB1), ATP-binding cassette subfamily G member 2 (ABCG2), and ATP-binding cassette subfamily C member 4 (ABCC4). Genetic polymorphisms (single-nucleotide polymorphisms) can impact transporter activity, leading to interindividual variability in the systemic and cellular pharmacokinetics of their substrates. This study assesses the impact of these transporters on moxifloxacin and ciprofloxacin (CIP) cellular accumulation in vitro, and the effect of common single-nucleotide polymorphisms in ABCB1 [c.1199G>A (rs2229109); common haplotype c.1236C>T (rs1128503), c.2677G>T/A (rs2032582), and c.3435C>T (rs1045642)] and ABCG2 [c.421C>A (rs2231142)]. Recombinant human embryonic kidney (HEK) cell lines overexpressing wild-type or variant transporters were generated via stable plasmid transfection. The impact of transporter overexpression on fluoroquinolone cell disposition was assessed through accumulation experiments in the presence of specific inhibitors to establish the link between transporter expression and differential accumulation. Results indicated that ABCB1 overexpression reduced moxifloxacin cellular concentration by 30% but inconsistently with that of CIP and that zosuquidar or elacridar reversed these effects. ABCG2 had no impact. ABCC4 markedly reduced CIP accumulation by 25%, even at the basal level, an effect reversed by MK517. Contrarily to the wild-type and the c.1199A carriers, ABCB1 CGT and TTT variants did not reduce antibiotic accumulation. In conclusion, moxifloxacin and CIP are substrates of the wild-type and 1199G>A ABCB1, while CGT and TTT haplotypes had a marginal impact on fluoroquinolone transport by ABCB1. CIP is a preferential ABCC4 substrate. Because of the large body distribution of these transporters, our findings may help rationalize their role and the impact of their polymorphisms in fluoroquinolone disposition in tissues and cells. SIGNIFICANCE STATEMENT: This study demonstrates that moxifloxacin and ciprofloxacin are substrates of ABCB1, with ciprofloxacin also transported by ABCC4. Specific ABCB1 polymorphisms (CGT and TTT haplotypes) reduce the ABCB1 transport capacity toward fluoroquinolones. These findings highlight the importance of considering ABCB1 and ABCC4 inducers or inhibitors, which may affect fluoroquinolone disposition in tissues and cells, as well as ABCB1 polymorphisms that could explain interindividual variability in pharmacokinetic profiles.

Tissue transglutaminase (TG2) is a multifunctional protein that can catalyze the cross-linking between proteins, and function as a G-protein. TG2's unregulated behaviour has been associated with fibrosis, celiac disease and cancer metastasis. Recently, small molecule irreversible inhibitors have been designed, bearing an electrophilic warhead that can react with the catalytic cysteine, abolishing TG2's catalytic and G-protein capabilities. Several research groups have converged on inhibitors comprising piperazine scaffolds, but no structure-activity relationships (SAR) of the piperazine core have been reported. In this study we synthesize a series of inhibitors with various diamino linkers, to understand what structural requirements are necessary for the core to help align the terminal acrylamide warhead in the optimal position. Kinetic evaluation using an in vitro biochemical assay provided the kinetic parameters k_inact and K_I for each inhibitor. This study revealed that adding a methyl group to the piperazine core can improve inhibitor efficiency.