Delving into the Latest Updates on S-49076 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

AXL x FGFR1 x FGFR2 x FGFR3 x c-Met

Action

inhibitors, antagonists

Mechanism

AXL inhibitors(AXL receptor tyrosine kinase inhibitors), FGFR1 antagonists(Fibroblast growth factor receptor 1 antagonists), FGFR2 antagonists(Fibroblast growth factor receptor 2 antagonists)

+ [2]

Therapeutic Areas

NeoplasmsNervous System DiseasesRespiratory Diseases+ [1]

Active Indication

GlioblastomaNon-Small Cell Lung Cancer

Inactive Indication

Liver Cancer

Originator Organization

Les Laboratoires Servier SAS

Active Organization

Les Laboratoires Servier SAS

Inactive Organization

Delpharm SAS

License Organization-

Drug Highest PhasePhase 2

First Approval Date-

RegulationSpecial Review Project (China)

Login to view timeline

Structure/Sequence

Molecular FormulaC22H22N4O4S

InChIKeyAREYWCZYVPSHGS-UHFFFAOYSA-N

CAS Registry1265965-22-7

View All Structures (2)

AXL, part of the TAM receptor tyrosine kinase family, plays a significant role in the growth and survival of various tissues and tumors, making it a critical target for cancer therapy. This study introduces a novel high-throughput virtual screening (HTVS) methodology that merges an AI-enhanced graph neural network, PLANET, with a geometric deep learning algorithm, DeepDock. Using this approach, we identified potent AXL inhibitors from our database. Notably, compound 9, with an IC₅₀ of 9.378 nM, showed excellent inhibitory activity, suggesting its potential as a candidate for further research. We also performed molecular dynamics simulations to explore the interactions between compound 9 and AXL, providing insights for future enhancements. This hybrid screening method proves effective in finding promising AXL inhibitors, and advancing the development of new cancer therapies.

01 Nov 2021·CPT: Pharmacometrics & Systems PharmacologyQ3 · MEDICINE

Modeling restoration of gefitinib efficacy by co‐administration of MET inhibitors in an EGFR inhibitor‐resistant NSCLC xenograft model: A tumor‐in‐host DEB‐based approach

Q3 · MEDICINE

ArticleOA

Author: Chenel, Marylore ; Fouliard, Sylvain ; Tosca, Elena M. ; Burbridge, Mike ; Gauderat, Glenn ; Magni, Paolo

AbstractMET receptor tyrosine kinase inhibitors (TKIs) can restore sensitivity to gefitinib, a TKI targeting epidermal growth factor receptor (EGFR), and promote apoptosis in non‐small cell lung cancer (NSCLC) models resistant to gefitinib treatment in vitro and in vivo. Several novel MET inhibitors are currently under study in different phases of development. In this work, a novel tumor‐in‐host modeling approach, based on the Dynamic Energy Budget (DEB) theory, was proposed and successfully applied to the context of poly‐targeted combination therapies. The population DEB‐based tumor growth inhibition (TGI) model well‐described the effect of gefitinib and of two MET inhibitors, capmatinib and S49076, on both tumor growth and host body weight when administered alone or in combination in an NSCLC mice model involving the gefitinib‐resistant tumor line HCC827ER1. The introduction of a synergistic effect in the combination DEB‐TGI model allowed to capture gefitinib anticancer activity enhanced by the co‐administered MET inhibitor, providing also a quantitative evaluation of the synergistic drug interaction. The model‐based comparison of the two MET inhibitors highlighted that S49076 exhibited a greater anticancer effect as well as a greater ability in restoring sensitivity to gefitinib than the competitor capmatinib. In summary, the DEB‐based tumor‐in‐host framework proposed here can be applied to routine combination xenograft experiments, providing an assessment of drug interactions and contributing to rank investigated compounds and to select the optimal combinations, based on both tumor and host body weight dynamics. Thus, the combination tumor‐in‐host DEB‐TGI model can be considered a useful tool in the preclinical development and a significant advance toward better characterization of combination therapies.

01 May 2021·Lung CancerQ2 · MEDICINE

Phase I results of S49076 plus gefitinib in patients with EGFR TKI-resistant non-small cell lung cancer harbouring MET/AXL dysregulation

Q2 · MEDICINE

Article

Author: Cattan, Valérie ; Lim, Wan-Teck ; Soo, Ross A ; Molina-Vila, Miguel A ; Park, Keunchil ; Chang, Gee-Chen ; Gandossi, Eric ; Darville, Hélène ; Curigliano, Giuseppe ; Sudey, Isabelle ; Viteri, Santiago ; Smutna, Veronika

BACKGROUNDMET and AXL dysregulation is reported as a bypass mechanism driving tumour progression in non-small cell lung cancer (NSCLC) with acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). This non-comparative phase I study investigated the combination of gefitinib with S49076, a MET/AXL inhibitor, in advanced EGFR TKI-resistant NSCLC patients with MET and/or AXL dysregulation.METHODSPatients received S49076 at escalating doses of 500 or 600 mg with a fixed dose of 250 mg gefitinib orally once daily in continuous 28day cycles. MET and AXL dysregulation and EGFR/T790M mutation status were centrally assessed in tumour biopsies at screening. Tumour response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST). EGFR TKI resistance mechanisms were analysed by next-generation sequencing. The clonal evolution of tumours was monitored with the analysis of circulating tumour DNA.RESULTSOf 92 pre-screened patients, 22 met the molecular inclusion criteria and 14 were included. The recommended dose was 600 mg daily S49076. Best overall responses were 2 partial responses (1 patient with MET dysregulation only, 1 MET and AXL co-dysregulation) and 8 patients with stable disease. Other potential concomitant mechanisms of resistance to EGFR TKI were identified in more than half of the included patients.CONCLUSIONSS49076 plus gefitinib demonstrated a good tolerability with limited anti-tumour activity. Due to the low number of eligible patients, no tendency in term of activity appeared in any specific molecular subset and the data did not allow for identification of AXL overexpression as an oncogenic driver.

100 Deals associated with S-49076

Login to view more data

R&D Status

10 top R&D records.

Login

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Glioblastoma	Phase 2	-	Les Laboratoires Servier SAS	-
Non-Small Cell Lung Cancer	Phase 2	-	Les Laboratoires Servier SAS	-
Liver Cancer	Phase 1	France	Les Laboratoires Servier SAS	-