Cancer cells require a massive supply of nutrients, including sugars and amino acids—the upregulation of transporters for each nutrient contributes to meet the demand. Distinct from glucose transporters, amino acid transporters include ones whose expression is specific to cancer cells. For example, LAT1 (SLC7A5) displays protein expression mostly limited to the plasma membrane of cancer cells. The exceptions are the placental barrier and the blood-brain barrier, where immunohistochemical and mass spectrometric studies have shown LAT1 expression, although their levels are supposed to be lower than those in cancers. The expression of LAT1 has been reported in cancers from various tissue origins, where high LAT1 expression is related to the poor prognosis of patients. LAT1 is essential for cancer cell growth because the pharmacologic inhibition and knockdown/knockout of LAT1 suppress the proliferation of cancer cells and the growth of xenograft tumors. The inhibition of LAT1 suppresses protein synthesis by downregulating the mTORC1 signaling pathway and mobilizing the general amino acid control (GAAC) pathway in cancer cells. LAT1 is, thus, a candidate molecular target for the diagnosis and therapeutics of cancers. ¹⁸F-labeled 3-fluoro-l-α-methyl-tyrosine (FAMT) is used as a LAT1-specific PET probe for cancer detection due to the LAT1 specificity of α-methyl aromatic amino acids. FAMT accumulation is cancer-specific and avoids non-cancer lesions, including inflammation, confirming the cancer-specific expression of LAT1 in humans. Due to the cancer-specific nature, LAT1 can also be used for cancer-specific delivery of anti-tumor agents such as l-para-boronophenylalanine used for boron neutron capture therapy and α-emitting nuclide-labeled LAT1 substrates developed for nuclear medicine treatment. Based on the importance of LAT1 in cancer progression, high-affinity LAT1-specific inhibitors have been developed for anti-tumor drugs. JPH203 (KYT0353) is such a compound designed based on the structure-activity relationship of LAT1 ligands. It is one of the highest-affinity inhibitors with less affecting other transporters. It suppresses tumor growth in vivo without significant toxicity in preclinical studies at doses enough to suppress tumor growth. In the phase-I clinical trial, JPH203 appeared to provide promising activity. Because the mechanisms of action of LAT1 inhibitors are novel, with or without combination with other anti-tumor drugs, they could contribute to the treatment of cancers that do not respond to current therapy. The LAT1-specific PET probe could also be used as companion diagnostics of the LAT1-targeting therapies to select patients to whom therapeutic benefits could be expected. Recently, the cryo-EM structure of LAT1 has been solved, which would facilitate the understanding of the mechanisms of the dynamic interaction of ligands and the binding site, and further designing new compounds with higher activity.

癌细胞需要大量的营养物质，包括糖和氨基酸——每种营养物质的转运蛋白的上调有助于满足需求。与葡萄糖转运蛋白不同，氨基酸转运蛋白包括其表达对癌细胞具有特异性的转运蛋白。例如，LAT1 (SLC7A5) 显示的蛋白质表达主要局限于癌细胞的质膜。胎盘屏障和血脑屏障例外，免疫组化和质谱研究显示 LAT1 表达，尽管它们的水平应该低于癌症中的水平。据报道，LAT1 的表达存在于各种组织来源的癌症中，其中 LAT1 的高表达与患者预后不良有关。LAT1 对癌细胞生长至关重要，因为 LAT1 的药理学抑制和敲低/敲除可抑制癌细胞的增殖和异种移植肿瘤的生长。LAT1 的抑制通过下调 mTORC1 信号通路和调动癌细胞中的一般氨基酸控制 (GAAC) 通路来抑制蛋白质合成。因此，LAT1 是癌症诊断和治疗的候选分子靶标。^{由于 α-甲基芳香族氨基酸的 LAT1 特异性， 18} F-标记的 3-氟-1 -α-甲基-酪氨酸 (FAMT) 被用作 LAT1 特异性 PET 探针用于癌症检测。FAMT 积累是癌症特异性的，可以避免非癌症病变，包括炎症，证实了 LAT1 在人类中的癌症特异性表达。由于癌症特异性，LAT1 还可用于癌症特异性递送抗肿瘤剂，例如l-对硼苯丙氨酸用于硼中子俘获疗法和为核医学治疗开发的α发射核素标记的 LAT1 底物。基于 LAT1 在癌症进展中的重要性，已开发出用于抗肿瘤药物的高亲和力 LAT1 特异性抑制剂。JPH203（KYT0353）就是这样一种基于LAT1配体的构效关系设计的化合物。它是亲和力最高的抑制剂之一，对其他转运蛋白的影响较小。它在体内抑制肿瘤生长在足以抑制肿瘤生长的剂量下，在临床前研究中没有显着毒性。在 I 期临床试验中，JPH203 似乎提供了有希望的活性。由于 LAT1 抑制剂的作用机制是新颖的，无论是否与其他抗肿瘤药物联合使用，它们都可能有助于治疗对当前疗法无反应的癌症。LAT1 特异性 PET 探针也可用作 LAT1 靶向疗法的伴随诊断，以选择有望获得治疗益处的患者。最近，LAT1的cryo-EM结构得到了解决，这将有助于理解配体和结合位点的动态相互作用机制，并进一步设计具有更高活性的新化合物。