Delving into the Latest Updates on Nanvuranlat with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [2]

Target

SLC7A5

Mechanism

SLC7A5 inhibitors(L-type amino acid transporter 1 inhibitors)

Therapeutic Areas

NeoplasmsDigestive System DisordersUrogenital Diseases

Active Indication

Biliary Tract NeoplasmsColorectal CancerRenal Cell Carcinoma

Inactive Indication-

Originator Organization

J-Pharma Co., Ltd.

Active Organization

J-Pharma Co., Ltd.

Inactive Organization-

Drug Highest PhasePhase 3

First Approval Date-

RegulationOrphan Drug (US)

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Structure

Molecular FormulaC23H19Cl2N3O4

InChIKeyXNRZJPQTMQZBCE-SFHVURJKSA-N

CAS Registry1037592-40-7

The glycoprotein CD98, or CD98 heavy chain (CD98hc), encoded by the SLC3A2 gene, plays a crucial role in cancer development and progression. CD98hc, forming heterodimeric complexes with various light chains, regulates neutral amino acid transport across cell membranes. The intricate interplay between CD98hc, integrins, and amino acid transporters shapes the tumor microenvironment and contributes to tumor growth. Elevated expression of CD98hc in various cancers correlates with poor prognosis, making it a potential prognostic marker. In colorectal cancer, CD98hc emerges as a potential therapeutic target, along with its partner LAT1, and inhibitors like JPH203 exhibit promise in preclinical studies. Targeting CD98hc/LAT1, alone or with conventional therapies, shows promise in inhibiting tumor growth. This review focuses on elucidating the multifaceted roles of CD98hc and its partner LAT1 in cancer, particularly its involvement in amino acid transport, signaling pathways, and its prognostic relevance in cancer.

01 Nov 2024·Biochemical and Biophysical Research Communications

JPH203 alleviates peritoneal fibrosis via inhibition of amino acid-mediated mTORC1 signaling

Article

Author: Dai, Junhao ; Yu, Zanzhe ; Zhang, Xuemei ; Wu, Tiangang ; Li, Jiayang ; Ning, Fengling ; Zhu, Nan ; Liu, Xin

BACKGROUND AND AIMSThe mesothelial-mesenchymal transition (MMT) of mesothelial cells has been recognized as a critical process during progression of peritoneal fibrosis (PF). Despite its crucial role in amino acid transport and metabolism, the involvement of L-type amino acid transporter 1 (LAT1) and the potential therapeutic role of its inhibitor, JPH203, in fibrotic diseases remain unexplored. Considering the paucity of research on amino acid-mediated mTORC1 activation in PF, our study endeavors to elucidate the protective effects of JPH203 against PF and explore the involvement of amino acid-mediated mTORC1 signaling in this context.METHODSWe established the transforming growth factor beta 1 (TGF-β1) induced MMT model in primary human mesothelial cells and the peritoneal dialysis fluid (PDF) induced PF model in mice. The therapeutic effects of JPH203 on PF were then examined on these two models by real-time quantitative polymerase chain reaction, western blotting, immunofluorescence staining, Masson's trichrome staining, H&E staining, picro-sirius red staining, and immunohistochemistry. The involvement of amino acid-mediated mTORC1 signaling was screened by RNA sequencing and further verified by western blotting in vitro.RESULTSLAT1 was significantly upregulated and JPH203 markedly attenuated fibrotic phenotype both in vitro and in vivo. RNA-seq unveiled a significant enrichment of mTOR signaling pathway in response to JPH203 treatment. Western blotting results indicated that JPH203 alleviates PF by inhibiting amino acid-mediated mTORC1 signaling, which differs from the direct inhibition observed with rapamycin.CONCLUSIONJPH203 alleviates PF by inhibiting amino acid-mediated mTORC1 signaling.

01 Oct 2024·Journal of Biological Chemistry

LAT1 supports mitotic progression through Golgi unlinking in an amino acid transport activity-independent manner

Article

Author: Saito, Youhei ; Nakayama, Yuji ; Yuki, Ryuzaburo ; Yanagida, Sakura

Amino acid transporters play a vital role in cellular homeostasis by maintaining protein synthesis. L-type amino acid transporter 1 (LAT1/SLC7A5/CD98lc) is a major transporter of large neutral amino acids in cancer cells because of its predominant expression. Although amino acid restriction with various amino acid analog treatments is known to induce mitotic defects, the involvement of amino acid transporters in cell division remains unclear. In this study, we identified that LAT1 is responsible for mitotic progression in a transport activity-independent manner. LAT1 knockdown activates the spindle assembly checkpoint, leading to a delay in metaphase. LAT1 maintains proper spindle orientation with confinement of the lateral cortex localization of the NuMA protein, which mediates the pulling force against the mitotic spindle toward the lateral cortex. Unexpectedly, JPH203, an inhibitor of LAT1 amino acid transport activity, does not affect mitotic progression. Moreover, the transport activity-deficient LAT1 mutant maintains the proper spindle orientation and mitotic progression. LAT1 forms a heterodimer with CD98 (SLC3A2/CD98hc) both in interphase and mitosis. Although CD98 knockdown decreases the plasma membrane localization of LAT1, it does not affect mitotic progression. LAT1 is localized to the Golgi and ER not only at the plasma membrane in interphase, and promotes Golgi unlinking during the mitotic entry, leading to centrosome maturation. These results suggest that LAT1 supports mitotic progression in an amino acid transport activity-independent manner and that Golgi-localized LAT1 is important for mitotic progression through the acceleration of Golgi unlinking and centrosome maturation. These findings reveal a novel LAT1 function in mitosis.

100 Deals associated with Nanvuranlat

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Biliary Tract Neoplasms	Phase 3	JP	J-Pharma Co., Ltd.	-
Colorectal Cancer	Phase 2	JP	J-Pharma Co., Ltd.	-
Colorectal Cancer	Phase 2	US	J-Pharma Co., Ltd.	-
Renal Cell Carcinoma	Phase 1	JP	J-Pharma Co., Ltd.	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


JPRN-UMIN000034080 (ASCO2023) Manual	Phase 2	Biliary Tract Neoplasms	104	Nanvuranlat	(nzlycyrpgr): HR = 0.439 (95% CI, 0.2254 - 0.8535), P-Value = 0.0131 View more	Positive	26 May 2023
				placebo
JPRN-UMIN000034080 (ASCO_GI2023) Manual	Phase 2	Biliary Tract Neoplasms	106	nanvuranlat	(tjxtkiudwq) = significant improvement lkrkwctazt (msujlckclf ) Met	Positive	24 Jan 2023
				placebo
JPRN-UMIN000016546 (ASCO2018)	Phase 1	HR-positive/HER2-low Solid Tumors	-	JPH203	(femtrxyxmq) = Common treatment-related adverse events were increased ALT/AST, malaise, nausea, hypertension, and grade 1 or grade 2 fevers. qipeqsvvde (iskchqeehm ) View more	Positive	01 Jun 2018
JPRN-UMIN000016546 (ASCO_GI2018)	Phase 1	HR-positive/HER2-low Solid Tumors	17	JPH203	(fdjumdxxgl) = Common treatment-related adverse events were increased ALT/AST, malaise, nausea, hypertension and fever of Grade 1 or 2. haawnkkwvy (wkhalxyqyr ) View more	Positive	26 Feb 2018