L-type amino acid transporters LAT1 (SLC7A5) and LAT2 (SLC7A8) facilitate the bidirectional transport of branched and aromatic amino acids (AAs) across the plasma membrane. LAT1 has emerged as a key therapeutic target in cancer due to its upregulation in different tumor types. We generated and characterized LAT1- and LAT2-expressing cells using the human MDST8 cell line lacking these transporters to evaluate the specificity and selectivity of the clinical candidate JPH203 and novel LAT1 inhibitors. Both LAT1 and LAT2 increased the expression of 4F2hc, a heavy chain protein essential for LAT1 functioning and AA transport. We show for the first time that two potent nanomolar LAT1 inhibitors, JPH203 and JX-078, can enter cells through LAT1-independent mechanisms and inhibit LAT1-mediated L-leucine efflux, giving rise to differential cell type and time-dependent effects on the AA metabolome and metabolic activity in cancer cells and human PBMCs. Intriguingly, the antiproliferative effects of JPH203 and JX-078 on MDST8 cells were LAT1-independent, showing also micromolar IC50 values in HT-29 and U937 cells that overexpress LAT1. We found notable differences in the bioavailability of LAT1 inhibitors in mice. Oral administration of JX-078 efficiently penetrated tissues and crossed the blood-brain barrier, leading to increased levels of inhibitory neurotransmitters glycine and GABA in the brain. This study demonstrates the utility of employing targeted metabolomics to interrogate LAT1/2 inhibitor selectivity in different physiological matrices in vitro, ex vivo and in vivo. Overall, our findings reveal LAT1-dependent and previously unrecognized LAT-independent effects of inhibitors believed to act specifically on LAT1.

2025-08-01·JOURNAL OF CHROMATOGRAPHY A

Study on dissociated states of twenty proteinogenic amino acids and their interactions with LAT1 by HPCE-IICRD

Article

作者: Huang, Tao ; Li, Jilun ; Ling, Xiaomei ; Liang, Chunsu

High performance capillary electrophoresis (HPCE) has been widely applied in the analysis of amino acids (AAs), but no studies on the HPCE analysis of dissociated states of AAs have been reported. Here, twenty proteingenic AAs were analyzed by the newly-developed universal interface-induced current detector (IICRD). Two or three current signal peaks were observed in current electrophoretograms (CR-EGs), while only one peak with low sensitivity can be obtained by DAD. The current signal peaks of AAs were accurately identified by adding charge-neutral marker, comparing current signal peaks at different pH conditions, also calculating by pK_a. The qualitative analysis indicated that the three current signal peaks of basic AAs were monovalent cations ([AA⁺]), charge-neutral forms ([AA^±]), and monovalent anions ([AA^-]) in order. Similarly, acidic AAs can be detected in three forms as [AA^±], [AA^-] and [AA^2-], while neutral AAs can be detected as [AA^±] and [AA^-]. Quantitative analysis showed that HPCE-IICRD can enhance the sensitivity of AAs to 40 μmol/L in LOD, with a linear range from 10^-6 mol/L to 10^-2 mol/L. Furthermore, interactions between different dissociated states of twenty AAs and l-type amino acid transporter (LAT1) were studied by combined application of NICCE method for the first time. The binding kinetic parameters and mole number of LAT1 on cell membranes can also be obtained. Besides, competitive binding experiments proved that JPH203 (LAT1-specific inhibitor) and leucine shared the same binding site. HPCE-IICRD provides a new method to reveal the interaction between different dissociated forms of AAs or other biomolecules and essential receptors.

2025-07-01·ADVANCED MATERIALS

Multiplex Methionine Modulating Hydrogel for Cancer Metabolic Therapy

Article

作者: Ma, Siyu ; Liu, Chang ; Ji, Xiaoyuan ; Chen, Nan ; Guo, Daoxia ; Zhu, Wen ; Song, Haiyun

Abstract:

The reliance on high levels of methionine by tumor cells provides an attractive target for cancer treatment. However, systemic methionine blockade may raise concerns about potential side effects given the broad and essential functions of methionine in cellular metabolism. Here, a combined drug delivery platform for multilayered constraint of methionine within tumor lesions is developed. Small molecule inhibitors PF9366 and adenosine dialdehyde are encapsulated by tumor cell‐targeting nanoparticles (NPs) to achieve a cascaded blockage of intracellular methionine metabolism. These NPs are further co‐loaded with the extracellular methionine uptake inhibitor JPH203 into a type of reactive oxygen species‐sensitive hydrogel, assembling the multiplex methionine modulating hydrogel (3 M Gel). In murine models of triple‐negative breast cancer (TNBC), hepatocellular carcinoma, and colorectal cancer, the in situ formed 3 M Gel exhibits superior efficacy in restricting S‐adenosyl methionine generation and histone methylation, stimulating immunogenic cell death in tumor cells, thereby eliciting potent innate and adaptive immune responses to restrain tumor progression. Moreover, remodeling of the tumor microenvironment by 3 M Gel overcomes immune checkpoint blockade resistance in TNBC. This study presents a localized triple regulation strategy and paves a new path for amino acid starvation‐based cancer therapy.

项与 Nanvuranlat 相关的新闻（医药）

2023-09-18

·生物谷

《自然·癌症》：华西医院团队破解癌症早期发展之谜，有望催生防癌新疗法

综上，该研究创建了两种新型mutp53荧光融合蛋白报告基因鼠，能可视化mutp53的分子功能，可在病理正常的组织中对早期癌前细胞进行特异性标记、追踪和靶向干预，为研究肿瘤早期演进过程铺平了道路。近期，四川大学华西生物治疗国家重点实验室汪源团队利用基因编辑技术，构建了两种突变P53（mutp53）荧光融合蛋白报告基因鼠，可模拟mutp53蛋白在体内的功能和动态，不仅能在包括脑瘤、肉瘤、淋巴瘤等多种恶性肿瘤形成前，组织病理学无明显异常的情况下，特异性地识别、标记出那些mutp53蛋白高积累的癌前细胞，还能追踪肿瘤发生发展全过程。此外，研究团队还在胸腺淋巴瘤模型中发现，mutp53蛋白高积累的癌前细胞存在独特的基因组特征，如调控氨基酸转运代谢的基因Ybx3表达上调。若在早期肿瘤发生过程中使用氨基酸转运抑制剂JPH203治疗，可有效抑制肿瘤发生并延长小鼠生存时间。研究成果发表在《自然·癌症》上，姚朋乐、肖鹏和黄宗瑶是论文的共同第一作者。论文首页截图 P53可以说是人类癌症中最常见的基因突变，一半以上的癌症中都存在mutp53。汪源团队既往研究发现，在恶性脑胶质瘤模型中，mutp53蛋白不仅会在终末期肿瘤中高度积累，也会在病理正常的脑组织的癌前细胞中高度积累，具有特异性地标记癌前细胞的潜力。于是，汪源团队就想利用mutp53蛋白的高度积累，来观察和量化肿瘤早期演变过程。不过传统的mutp53检测，主要还是靠免疫组化，如何在病理正常的组织中观察、追踪并分离那些mutp53蛋白高度累积且最终会发展成肿瘤的癌前细胞，是个难题。更难的是，当时根本没有研究肿瘤发生与演进的肿瘤基因工程小鼠模型。那怎么办？自己造呗。经过不断的尝试，汪源团队最终利用基因编辑技术构建了两种mutp53融合蛋白报告基因鼠，p53-mCherry-KI（PC）和p53R172H-Akaluc（PAL），前者可以观察肿瘤和癌前细胞中的mutp53蛋白积累程度，并对癌前细胞进行流式分选，后者能通过新型荧光素酶系统，标记深层组织中的微量细胞。两种mutp53融合蛋白报告基因鼠在本研究中，汪源团队先是通过体外实验证明了PAL和PC均能很好地模拟热门mutp53（如p53R172H）的分子动力学和功能。随后，通过小鼠杂交获得的包括脑瘤、肉瘤、淋巴瘤等多种恶性实体瘤小鼠模型，也证明了PAL和PC中的mutp53单独或联合其他致癌基因可以驱动多种类型肿瘤的发生。此外，汪源团队还在多种肿瘤细胞中观察到PAL和PC融合蛋白的特异性积累，能通过PAL和PC可视化追踪脑瘤、肉瘤及恶性淋巴瘤等肿瘤的发生发展过程。接下来，为了探究PAL和PC能否追踪到正常组织中的癌前细胞，汪源团队决定用PCL小鼠（即通过PAL和PC杂交构建的Trp53PAL/PC小鼠模型，会发展为胸腺淋巴瘤）进行一次示范性研究。在构建的13只PCL小鼠中有9只在不同年龄段进展为胸腺淋巴瘤。起初，汪源团队只能在这些小鼠胸腺区域发现一些基础水平的、分布均匀的发光信号（RSI），随着小鼠年龄增长，这些信号开始变强，最大强度是基础水平的5-6倍。为了更好地量化发光强度，研究人员将高于基础水平2-3倍的RSI定义为发光灶，在发光灶出现后的4-6周里，所有小鼠均会进展为胸腺淋巴瘤。 13只PCL小鼠的RSI变化情况进一步，汪源团队想知道发光灶能否代表癌前病变，于是就对6只首次检测到发光灶的小鼠进行了组织学分析。结果发现，出现发光灶时，尽管小鼠胸腺大小和形态与同龄对照小鼠没有区别，但实际上已经出现了一些mutp53阳性异常细胞（细胞核形态改变）。这些异常细胞会在接下来的4-6周里高度积累，最终发展成小肿瘤（RSI=3.8）。也就是说，发光灶可以作为癌前病变的信号。组织学分析结果利用这些发光灶，研究人员可以在肿瘤发生前1-2月内，对癌前细胞进行标记。接下来的流式分选和T细胞受体测序结果也显示，即使在癌前细胞比例较低的情况下，PAL和PC依然可以将其进行特异性标记。现在工具问题解决了，那么接下来汪源团队需要解决的是，在癌症发生前，能否通过预防性治疗抑制肿瘤发生呢？为了解决这一问题，汪源团队对流式分选获得的mutp53高积累癌前细胞进行单细胞转录组分析。结果发现，这些癌前细胞具有广泛的染色体拷贝数变异以及独特的不同于正常细胞的转录组特征，如调控氨基酸转运、代谢的相关基因Ybx3表达上调。进一步，汪源团队发现，Ybx3可以通过控制其下游氨基酸转运蛋白Lat1/CD98来调控氨基酸的代谢。于是研究人员以Ybx3-Lat1/CD98为干预靶标，利用已经进入1期临床试验的Lat1/CD98抑制剂JPH203对PCL小鼠进行预防性治疗。具体来说，一旦出现发光灶，就开始治疗。结果显示，所有接受JPH203治疗的小鼠，发光信号以肉眼可见的速度变弱，2天内就能降到1RSI以下。此外，相较同龄对照小鼠，JPH203治疗组的中位生存期增加了71%。更重要的是，一半以上的小鼠都未进展为胸腺淋巴瘤。不过需要注意的是，JPH203只在早期，即出现发光灶时进行干预治疗才有效，当RSI>6时，接受JPH203治疗的小鼠没有任何生存获益。早期肿瘤发生过程中使用JPH203治疗，可有效抑制肿瘤发生并延长小鼠生存时间综上，该研究创建了两种新型mutp53荧光融合蛋白报告基因鼠，能可视化mutp53的分子功能，可在病理正常的组织中对早期癌前细胞进行特异性标记、追踪和靶向干预，为研究肿瘤早期演进过程铺平了道路。

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适应症	最高研发状态	国家/地区	公司	日期
胆道癌	临床3期	日本	J-Pharma Co., Ltd.	-
结直肠癌	临床2期	美国	J-Pharma Co., Ltd.	-
结直肠癌	临床2期	日本	J-Pharma Co., Ltd.	-
肾细胞癌	临床1期	日本	J-Pharma Co., Ltd.	-
原发性硬化性胆管炎	临床前	日本	J-Pharma Co., Ltd.	2025-02-01

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


JPRN-UMIN000034080 (ASCO 12023 \| ASCO 22023) 人工标引	临床2期	胆道癌	104	Nanvuranlat	遞繭繭夢憲獵齋鏇膚衊(糧糧夢餘齋膚糧齋鑰壓): HR = 0.439 (95% CI, 0.2254 ~ 0.8535), P-Value = 0.0131 更多	积极	2023-05-26
				placebo
JPRN-UMIN000034080 (ASCO_GI2023) 人工标引	临床2期	胆道癌	106	nanvuranlat	鏇遞築夢醖鬱憲積鏇遞(鬱衊憲積遞鹽鹽壓膚蓋) = significant improvement 鹹醖衊鹽鑰獵築顧艱襯 (築製鹹壓窪鬱獵簾鹽廠 ) 达到	积极	2023-01-24
				placebo
JPRN-UMIN000016546 (ASCO2018)	临床1期	HR阳性/HER2低表达实体瘤	-	JPH203	鏇鹽衊範製選醖網願獵(壓網獵鑰餘簾鏇壓簾憲) = Common treatment-related adverse events were increased ALT/AST, malaise, nausea, hypertension, and grade 1 or grade 2 fevers. 遞製襯範衊餘艱鏇窪鑰 (鏇繭窪醖觸壓構鏇鬱觸 ) 更多	积极	2018-06-01