Delving into the Latest Updates on JNJ-38877605 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

c-Met

Mechanism

c-Met inhibitors(Hepatocyte growth factor receptor inhibitors)

Therapeutic Areas

Neoplasms

Active Indication-

Inactive Indication

Solid tumor

Originator Organization

Johnson & Johnson

Active Organization-

Inactive Organization

Johnson & Johnson Pharmaceutical Research & Development LLCOrtho Biotech, Inc.

Drug Highest PhaseDiscontinuedPhase 1

First Approval Date-

Regulation-

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Structure

Molecular FormulaC19H13F2N7

InChIKeyJRWCBEOAFGHNNU-UHFFFAOYSA-N

CAS Registry943540-75-8

The receptor tyrosine kinase c-Met is elaborated in embryogenesis, morphogenesis, metabolism, cell growth, and differentiation.JNJ38877605 (JNJ) is an inhibitor of c-Met with anti-tumor activity.The c-Met expression and its role in adipocyte differentiation are unknown.Here, we investigated the c-Met expression and phosphorylation, knockdown (KD) effects, and pharmacol. inhibition of c-Met by JNJ on fat accumulation in murine preadipocyte 3T3-L1 cells.During 3T3-L1 preadipocyte differentiation, strikingly, c-Met expression at the protein and mRNA levels and the protein phosphorylation on Y1234/1235 and Y1349 is crucial for inducing its kinase catalytic activity and activating a docking site for signal transducers were increased in a time-dependent manner.Of note, JNJ treatment at 20μM that strongly inhibits c-Met phosphorylation without altering its total expression resulted in less lipid accumulation and triglyceride (TG) content with no cytotoxicity.JNJ further reduced the expression of adipogenic regulators, including CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), fatty acid synthase (FAS), acetyl CoA carboxylase (ACC), and perilipin A.Moreover, JNJ treatment increased cAMP-activated protein kinase (AMPK) and liver kinase B-1 (LKB-1) phosphorylation but decreased ATP levels.Significantly, KD of c-Met suppressed fat accumulation and triglyceride (TG) quantity and reduced the expression of C/EBP-α, PPAR-γ, FAS, ACC, and perilipin A.Collectively, the present results demonstrate that c-Met is a novel, highly conserved mediator of adipogenesis regulating lipid accumulation in murine adipocytes.

01 Feb 2020·Archives of Biochemistry and BiophysicsQ3 · BIOLOGY

Dynasore potentiates c-Met inhibitors against hepatocellular carcinoma through destabilizing c-Met

Q3 · BIOLOGY

Article

Author: Wu, Yueguang ; Wang, Shanshan ; Sun, Qianhui ; Zhang, Yingqiu ; Liu, Shuyan ; Liu, Fang ; Zaky, Mohamed Y ; Dong, Weijie ; Guo, Dong ; Zhang, Yang ; Wang, Taishu ; Wang, Duchuang ; Liu, Xiuxiu ; Li, Qiong ; Zhang, Jinrui ; Liu, Han ; Liu, Zhenhua

c-Met receptor is frequently overexpressed in hepatocellular carcinoma and thus considered as an attractive target for pharmacological intervention with small molecule tyrosine kinase inhibitors. Albeit with the development of multiple c-Met inhibitors, none reached clinical application in the treatment of hepatoma so far. To improve the efficacy of c-Met inhibitors towards hepatocellular carcinoma, we investigated the combined effects of the dynamin inhibitor dynasore with several c-Met inhibitors, including tivantinib, PHA-665752, and JNJ-38877605. We provide several lines of evidence that dynasore enhanced the inhibitory effects of these inhibitors on hepatoma cell proliferation and migration, accompanied with increased cell cycle arrest and apoptosis. Mechanically, the combinatorial treatments decreased c-Met levels and hence markedly disrupted downstream signaling, as revealed by the dramatically declined phosphorylation of AKT and MEK. Taken together, our findings demonstrate that the candidate agent dynasore potentiated the inhibitory effects of c-Met inhibitors against hepatoma cells and will shed light on the development of novel therapeutic strategies to target c-Met in the clinical management of hepatocellular carcinoma patients.

19 Nov 2018·Chemical Research in ToxicologyQ3 · MEDICINE

Evaluation of Deuterium-Labeled JNJ38877605: Pharmacokinetic, Metabolic, and in Vivo Antitumor Profiles

Q3 · MEDICINE

Article

Author: Ai, Jing ; Duan, Wenhu ; Sun, Yiming ; Peng, Xia ; Zhan, Zhengsheng

c-Met inhibitor JNJ38877605 has proven curative as an antitumor agent, while its clinical study was terminated due to renal toxicity. It was reported that the renal toxicity was caused by the poor solubility of its aldehyde oxidase (AO) metabolites. Therefore, blocking AO oxidation of JNJ38877605 might diminish the toxic metabolites and overcome the renal toxicity. Compound 3, the AO metabolic site deuterated JNJ38877605, was then synthesized as the target molecule. In vitro monkey liver S9 fraction incubation of 3 manifested that the renal toxic metabolite M2-2 was significantly reduced, which connoted that this deuteration has partly blocked AO oxidation. After po. nasal gavage to cynomolgus monkeys, compound 3 revealed decreased AO metabolites M2-2 and M3-2 in the plasma as well as 1.88-fold AUC and 1.56-fold C_max compared with JNJ38877605, indicating that deuterium replacement significantly blocked AO metabolism in vivo. Besides, metabolic profiles of 3 were investigated by analysis of the plasma and the urine of the po. administrated cynomolgus monkeys. Moreover, after oral administration to the EBC-1 tumor-bearing nude mice, compound 3 exhibited a better antitumor efficacy than JNJ38877605. In conclusion, deuteration on the AO metabolic site of JNJ38877605 improved its AO metabolism, oral exposure, as well as in vivo antitumor efficacy.

100 Deals associated with JNJ-38877605

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