Structure-guided targeting of the LAT1-4F2hc amino acid transporter in cancer and brain disorders

Vollständiger Abstract

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Abstract The heterodimeric amino acid transporter L-type amino acid transporter 1 (LAT1)-4F2hc (SLC7A5-SLC3A2) is a key regulator of large neutral amino acid exchange, linking extracellular nutrient availability to intracellular growth signaling. It is physiologically enriched at the blood-brain barrier (BBB) and in proliferative tissues but is broadly upregulated in cancer, where it supports metabolic reprogramming and mechanistic target of rapamycin complex 1 (mTORC1)-driven oncogenic growth. These properties make LAT1-4F2hc both a metabolic vulnerability in tumors and a promising gateway for central nervous system (CNS) drug delivery. Recent cryo-electron microscopy (cryo-EM) structures have resolved LAT1-4F2hc in multiple conformational states, defining its alternating-access mechanism, substrate recognition determinants, and allosteric gating network. These insights have enabled structure-guided, conformation-selective drug design, yielding substrate-mimetic inhibitors and state-stabilizing compounds such as JPH203 (nanvuranlat), now in clinical evaluation. Conversely, the same transport cycle can be exploited at the BBB to enhance brain delivery of LAT1-utilizing prodrugs, including l -dihydroxyphenylalanine (L-DOPA) and emerging therapeutic conjugates. Here, we integrate structural biology, nutrient sensing, and pharmacology to highlight conformational targeting strategies for both anticancer therapy and CNS drug delivery, and discuss key translational challenges such as metabolic compensation, selectivity, and pharmacokinetics.