Conserved allosteric inhibition mechanism in SLC1 transporters.

Excitatory amino acid transporter 1 (EAAT1) is a glutamate transporter belonging to the SLC1 family of solute carriers. It plays a key role in the regulation of the extracellular glutamate concentration in the mammalian brain. The structure of EAAT1 was determined in complex with UCPH-101, apotent, non-competitive inhibitor of EAAT1.

Alanine serine cysteine transporter (ASCT) substrate binding site properties probed with hydroxyhomoserine esters.

The glutamine transporter ASCT2 is highly overexpressed in cancer cells. Block of glutamine uptake by ASCT2 is a potential strategy to inhibit growth of cancer cells. However, pharmacology of the ASCT2 binding site is not well established.

Rational design of ASCT2 inhibitors using an integrated experimental-computational approach.

ASCT2 (SLC1A5) is a sodium-dependent neutral amino acid transporter that controls amino acid homeostasis in peripheral tissues. In cancer, ASCT2 is up-regulated where it modulates intracellular glutamine levels, fueling cell proliferation. Nutrient deprivation via ASCT2 inhibition provides a potential strategy for cancer therapy.

SLC16 Family: From Atomic Structure to Human Disease.

The solute carrier 16 (SLC16) family represents a diverse group of membrane proteins mediating the transport of monocarboxylates across biological membranes. Family members show a variety of functional roles ranging from nutrient transport and intracellular pH regulation to thyroid hormone homeostasis. Changes in the expression levels and transport function of certain SLC16 transporters are manifested in severe health disorders including cancer, diabetes, and neurological disorders.

Interaction of the neutral amino acid transporter ASCT2 with basic amino acids.

Glutamine transport across cell membranes is performed by a variety of transporters, including the alanine serine cysteine transporter 2 (ASCT2). The substrate-binding site of ASCT2 was proposed to be specific for small amino acids with neutral side chains, excluding basic substrates such as lysine. A series of competitive inhibitors of ASCT2 with low µM affinity were developed previously, on the basis of the 2,4-diaminobutyric acid (DAB) scaffold with a potential positive charge in the side chain.

Advances and Challenges in Rational Drug Design for SLCs.

There are over 420 human solute carrier (SLC) transporters from 65 families that are expressed ubiquitously in the body. The SLCs mediate the movement of ions, drugs, and metabolites across membranes and their dysfunction has been associated with a variety of diseases, such as diabetes, cancer, and central nervous system (CNS) disorders. Thus, SLCs are emerging as important targets for therapeutic intervention.

Novel alanine serine cysteine transporter 2 (ASCT2) inhibitors based on sulfonamide and sulfonic acid ester scaffolds.

The neutral amino acid transporter alanine serine cysteine transporter 2 (ASCT2) belongs to the solute carrier 1 (SLC1) family of transport proteins and transports neutral amino acids, such as alanine and glutamine, into the cell in exchange with intracellular amino acids. This amino acid transport is sodium dependent, but not driven by the transmembrane Na concentration gradient. Glutamine transport by ASCT2 is proposed to be important for glutamine homoeostasis in rapidly growing cancer cells to fulfill the energy and nitrogen demands of these cells.

Homology Modeling Informs Ligand Discovery for the Glutamine Transporter ASCT2.

The Alanine-Serine-Cysteine transporter (SLC1A5, ASCT2), is a neutral amino acid exchanger involved in the intracellular homeostasis of amino acids in peripheral tissues. Given its role in supplying glutamine to rapidly proliferating cancer cells in several tumor types such as triple-negative breast cancer and melanoma, ASCT2 has been identified as a key drug target. Here we use a range of computational methods, including homology modeling and ligand docking, in combination with cell-based assays, to develop hypotheses for structure-function relationships in ASCT2.

Angiomotin stabilization by tankyrase inhibitors antagonizes constitutive TEAD-dependent transcription and proliferation of human tumor cells with Hippo pathway core component mutations.

The evolutionarily conserved Hippo inhibitory pathway plays critical roles in tissue homeostasis and organ size control, while mutations affecting certain core components contribute to tumorigenesis. Here we demonstrate that proliferation of Hippo pathway mutant human tumor cells exhibiting high constitutive TEAD transcriptional activity was markedly inhibited by dominant negative TEAD4, which did not inhibit the growth of Hippo wild-type cells with low levels of regulatable TEAD-mediated transcription. The tankyrase inhibitor, XAV939, identified in a screen for inhibitors of TEAD transcriptional activity, phenocopied these effects independently of its other known functions by stabilizing angiomotin and sequestering YAP in the cytosol.