Structure activity relationships of benzylproline-derived inhibitors of the glutamine transporter ASCT2.

The glutamine transporter ASCT2 has been identified as a promising target to inhibit rapid growth of cancer cells. However, ASCT2 pharmacology is not well established. In this report, we performed a systematic structure activity analysis of a series of substituted benzylproline derivatives. Substitutions on the phenyl ring resulted in compounds with characteristics of ASCT2 inhibitors. Apparent binding affinity increased with increasing hydrophobicity of the side chain. In contrast, interaction of the ASCT2 binding site with specific positions on the phenyl ring was not observed. The most potent compound inhibits the ASCT2 anion conductance with a Ki of 3µM, which is in the same range as that of more bulky and higher molecular weight inhibitors recently reported by others. The experimental results are consistent with computational analysis based on docking of the inhibitors against an ASCT2 homology model. The benzylproline scaffold provides a valuable tool for further improving binding potency of future ASCT2 inhibitors.

Ligand Discovery for the Alanine-Serine-Cysteine Transporter (ASCT2, SLC1A5) from Homology Modeling and Virtual Screening.

The Alanine-Serine-Cysteine transporter ASCT2 (SLC1A5) is a membrane protein that transports neutral amino acids into cells in exchange for outward movement of intracellular amino acids. ASCT2 is highly expressed in peripheral tissues such as the lung and intestines where it contributes to the homeostasis of intracellular concentrations of neutral amino acids. ASCT2 also plays an important role in the development of a variety of cancers such as melanoma by transporting amino acid nutrients such as glutamine into the proliferating tumors. Therefore, ASCT2 is a key drug target with potentially great pharmacological importance. Here, we identify seven ASCT2 ligands by computational modeling and experimental testing. In particular, we construct homology models based on crystallographic structures of the aspartate transporter GltPh in two different conformations. Optimization of the models' binding sites for protein-ligand complementarity reveals new putative pockets that can be targeted via structure-based drug design. Virtual screening of drugs, metabolites, fragments-like, and lead-like molecules from the ZINC database, followed by experimental testing of 14 top hits with functional measurements using electrophysiological methods reveals seven ligands, including five activators and two inhibitors. For example, aminooxetane-3-carboxylate is a more efficient activator than any other known ASCT2 natural or unnatural substrate. Furthermore, two of the hits inhibited ASCT2 mediated glutamine uptake and proliferation of a melanoma cancer cell line. Our results improve our understanding of how substrate specificity is determined in amino acid transporters, as well as provide novel scaffolds for developing chemical tools targeting ASCT2, an emerging therapeutic target for cancer and neurological disorders.

Preeclampsia Among African American Pregnant Women: An Update on Prevalence, Complications, Etiology, and Biomarkers.

IMPORTANCE: Preeclampsia is a devastating disease of pregnancy associated with increased risk of fetal and maternal complications. African American pregnant women have a high prevalence of preeclampsia, but there is a need of systemic analyses of this high-risk group regarding complications, etiology, and biomarkers. OBJECTIVE: The aim of this study was to provide a synopsis of current research of preeclampsia specifically related to African American women. EVIDENCE ACQUISITION: A comprehensive search was performed in the bibliographic database PubMed with keywords "preeclampsia" and "African American." RESULTS: African American women with preeclampsia were at an increased risk of preterm birth, which resulted in low-birth-weight infants. Intrauterine fetal death among African American preeclamptic patients occurs at twice the rate as in other races. On the maternal side, African American mothers with preeclampsia have more severe hypertension, antepartum hemorrhage, and increased mortality. Those who survive preeclampsia have a high risk of postpartum cardiometabolic disease. Preexisting conditions (eg, systemic lupus erythematosus) and genetic mutations (eg, sickle cell disease in the mother, FVL or APOL1 mutations in the fetus) may contribute to the higher prevalence and worse outcomes in African American women. Many blood factors, for example, the ratio of proteins sFlt/PlGF, hormones, and inflammatory factors, have been studied as potential biomarkers for preeclampsia, but their specificity needs further investigation. CONCLUSIONS: Further studies of preeclampsia among African American women addressing underlying risk factors and etiologies, coupled with identification of preeclampsia-specific biomarkers allowing early detection and intervention, will significantly improve the clinical management of this devastating disease.