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

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.

13 Sep 2024·Clinical Cancer Research

A Phase II Placebo-Controlled Study of the Effect and Safety of Nanvuranlat in Patients with Advanced Biliary Tract Cancers Previously Treated by Systemic Chemotherapy

Article

Author: Yokoyama, Naoyuki ; Nishina, Tomohiro ; Ohkawa, Kazuyoshi ; Sasaki, Takashi ; Nakai, Yousuke ; Ueno, Makoto ; Furuse, Junji ; Ikeda, Masafumi ; Takehara, Tetsuo ; Okano, Naohiro ; Morizane, Chigusa ; Sugimori, Kazuya ; Todaka, Akiko ; Yamamoto, Kouji ; Furukawa, Masayuki ; Hara, Kazuo

AbstractPurpose:To evaluate the efficacy and safety of nanvuranlat [an L-type amino acid transporter 1 inhibitor] monotherapy as a later-line treatment in advanced, metastatic, and refractory biliary tract cancers.Patients and Methods:A multicenter, randomized, double-blind, placebo-controlled phase II study was conducted across fourteen leading Japanese cancer centers and hospitals. Nanvuranlat 25 mg/m2/day or placebo was given intravenously in cycles of 5 consecutive days, followed by 9 days off. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival and disease control rate. Subgroup analysis was performed in patients with high L-type amino acid transporter 1 expression and biliary tract cancer subtypes.Results:A total of 211 patients were screened, of which 105 eligible patients were randomized. Among these, 70 received nanvuranlat and 35 received placebo. Nanvuranlat demonstrated an improvement in PFS when compared with placebo (HR, 0.56; 95% confidence interval, 0.34–0.90; P = 0.02). Grade 3 or higher adverse events were reported in 30.0% and 22.9% of those in the nanvuranlat and placebo groups, respectively. The overall survival was not statistically different between nanvuranlat- and placebo-treated patients. An exploratory analysis indicated that nanvuranlat is warranted to evaluate its long-term clinical benefit in patients with intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer.Conclusions:Compared with placebo, nanvuranlat improved PFS in patients with advanced and refractory biliary tract cancer with an acceptable safety profile. Further studies of this promising compound are warranted in the population of patients who are exhausted from treatment options.

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.	-
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	(uhftnxcyyt): 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	(kjsjyyivcf) = significant improvement rqrmrzphwz (kciztxgixe ) Met	Positive	24 Jan 2023
				placebo
JPRN-UMIN000016546 (ASCO2018)	Phase 1	HR-positive/HER2-low Solid Tumors	-	JPH203	(mubcytnfyb) = Common treatment-related adverse events were increased ALT/AST, malaise, nausea, hypertension, and grade 1 or grade 2 fevers. vijtuqcytv (rbojsccbkn ) View more	Positive	01 Jun 2018
JPRN-UMIN000016546 (ASCO_GI2018)	Phase 1	HR-positive/HER2-low Solid Tumors	17	JPH203	(vsppnjgpxn) = Common treatment-related adverse events were increased ALT/AST, malaise, nausea, hypertension and fever of Grade 1 or 2. zrvjtzfnfj (xbjggecgkj ) View more	Positive	26 Feb 2018