Delving into the Latest Updates on MK-2461 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

PDGFRβ x c-Met

Action

inhibitors

Mechanism

PDGFRβ inhibitors(Platelet-derived growth factor receptor beta inhibitors), c-Met inhibitors(Hepatocyte growth factor receptor inhibitors)

Therapeutic Areas

NeoplasmsDigestive System DisordersEndocrinology and Metabolic Disease

Active Indication-

Inactive Indication

Advanced cancerAdvanced Malignant Solid NeoplasmNeoplasms+ [2]

Originator Organization

Merck Sharp & Dohme Corp.

Active Organization-

Inactive Organization

Merck GmbH

Merck Sharp & Dohme Corp.

Merck & Co., Inc.

+ [1]

License Organization-

Drug Highest PhaseDiscontinuedPhase 1/2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC24H25N5O5S

InChIKeyJGEBLDKNWBUGRZ-HXUWFJFHSA-N

CAS Registry917879-39-1

Abstractc‐Hepatocyte growth factor receptor (Met) inhibitors have demonstrated clinical benefits in some types of solid tumors. However, the efficacy of c‐Met inhibitors in esophageal squamous cell carcinoma (ESCC) remains unclear. In this study, we discovered that c‐Met inhibitors induced “Signal Transducer and Activator of Transcription (STAT3)‐addiction” in ESCC cells, and the feedback activation of STAT3 in ESCC cells limits the tumor response to c‐Met inhibition. Mechanistically, c‐Met inhibition increased the autocrine of several cytokines, including CCL2, interleukin 8, or leukemia inhibitory factor, and facilitated the interactions between the receptors of these cytokines and Janus Kinase1/2 (JAK1/2) to resultantly activate JAKs/STAT3 signaling. Pharmacological inhibition of c‐Met together with cytokines/JAKs/STAT3 axis enhanced cancer cells regression in vitro. Importantly, combined c‐Met and STAT3 inhibitors synergistically suppressed tumor growth and promoted the apoptosis of tumor cells without producing systematic toxicity. These findings suggest that inhibition of the STAT3 feedback loop may augment the response to c‐Met inhibitors via the STAT3‐mediated oncogene addiction in ESCC cells.

14 Mar 2019·Current Pharmaceutical DesignQ4 · MEDICINE

Targeting the C-MET/HGF Signaling Pathway in Pancreatic Ductal Adenocarcinoma

Q4 · MEDICINE

Review

Author: Avan, Amir ; Ghanaatgar-Kasbi, Sadaf ; Khorrami, Shadi ; Aledavoud, Seyed A. ; Ferns, Gordon A.

The c-mesenchymal-epithelial transition factor (c-MET) is involved in the tumorigenesis of various cancers. HGF/Met inhibitors are now attracting considerable interest due to their anti-tumor activity in multiple malignancies such as pancreatic cancer. It is likely that within the next few years, HGF/Met inhibitors will become a crucial component for cancer management. In this review, we summarize the role of HGF/Met pathway in the pathogenesis of pancreatic cancer, with particular emphasize on HGF/Met inhibitors in the clinical setting, including Cabozantinib (XL184, BMS-907351), Crizotinib (PF-02341066), MK-2461, Merestinib (LY2801653), Tivantinib (ARQ197), SU11274, Onartuzumab (MetMab), Emibetuzumab (LY2875358), Ficlatuzumab (AV- 299), Rilotumumab (AMG 102), and NK4 in pancreatic cancer.

01 Feb 2019·British Journal of CancerQ1 · MEDICINE

Drug sensitivity testing on patient-derived sarcoma cells predicts patient response to treatment and identifies c-Sarc inhibitors as active drugs for translocation sarcomas

Q1 · MEDICINE

Article

Author: Bernhardsson, Edvin ; Östling, Päivi ; Bauer, Henrik ; Brodin, Bertha A ; Papakonstantinou, Antroula ; Lidbrink, Elisabet ; Wilson, Jennifer N ; Tsagkozis, Panagiotis ; Porovic, Edvin ; Kallioniemi, Olli ; Wennerberg, Krister ; Moens, Lotte N ; Potdar, Swapnil ; Hesla, Asle ; von Sivers, Karin ; Brosjö, Otte ; Ma, Limin ; Stragliotto, Christina Linder ; Wejde, Johan

BACKGROUNDHeterogeneity and low incidence comprise the biggest challenge in sarcoma diagnosis and treatment. Chemotherapy, although efficient for some sarcoma subtypes, generally results in poor clinical responses and is mostly recommended for advanced disease. Specific genomic aberrations have been identified in some sarcoma subtypes but few of them can be targeted with approved drugs.METHODSWe cultured and characterised patient-derived sarcoma cells and evaluated their sensitivity to 525 anti-cancer agents including both approved and non-approved drugs. In total, 14 sarcomas and 5 healthy mesenchymal primary cell cultures were studied. The sarcoma biopsies and derived cells were characterised by gene panel sequencing, cancer driver gene expression and by detecting specific fusion oncoproteins in situ in sarcomas with translocations.RESULTSSoft tissue sarcoma cultures were established from patient biopsies with a success rate of 58%. The genomic profile and drug sensitivity testing on these samples helped to identify targeted inhibitors active on sarcomas. The cSrc inhibitor Dasatinib was identified as an active drug in sarcomas carrying chromosomal translocations. The drug sensitivity of the patient sarcoma cells ex vivo correlated with the response to the former treatment of the patient.CONCLUSIONSOur results show that patient-derived sarcoma cells cultured in vitro are relevant and practical models for genotypic and phenotypic screens aiming to identify efficient drugs to treat sarcoma patients with poor treatment options.

100 Deals associated with MK-2461

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Pancreatic Cancer	Phase 2	Japan	Tohoku University School of Medicine	01 Aug 2015
Advanced Malignant Solid Neoplasm	Phase 2	-	Merck Sharp & Dohme Corp.	01 Jun 2007
Advanced cancer	Phase 2	-	Merck Sharp & Dohme Corp.	01 Feb 2007
Neoplasms	Phase 2	United States	Merck GmbH	-
Neoplasms	Phase 2	United States	Merck GmbH	-
Solid tumor	Phase 2	Japan	Merck GmbH	-