Delving into the Latest Updates on MK-2461 with Synapse

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 Apr 2017·PancreasQ3 · MEDICINE

MK2461, a Multitargeted Kinase Inhibitor, Suppresses the Progression of Pancreatic Cancer by Disrupting the Interaction Between Pancreatic Cancer Cells and Stellate Cells

Q3 · MEDICINE

Article

Author: Katayose, Yu ; Terasaki, Tetsuya ; Unno, Michiaki ; Kawasaki, Shuhei ; Masuda, Kunihiro ; Douchi, Daisuke ; Tachikawa, Masanori ; Egawa, Shinichi ; Fukase, Koji ; Inoue, Koetsu ; Ohtsuka, Hideo ; Kawaguchi, Kei ; Shijo, Masahiro ; Naitoh, Takeshi ; Motoi, Fuyuhiko

OBJECTIVESPlatelet-derived growth factor receptor beta (PDGFRβ) and hepatocyte growth factor receptor (MET) expressed on pancreatic stellate cells (PSCs) are suggested as important components modulating the interactions between pancreatic cancer cells (PCCs) and PSCs. The objective of this study is to clarify the effect of MK2461, a multikinase inhibitor targeting MET and PDGFRβ, on the interaction between PCCs and PSCs.METHODSIn this study, we profiled the expression of receptor tyrosine kinases (including PDGFRβ and MET) in pancreatic cancer with quantitative targeted absolute proteomics using liquid chromatography tandem mass spectrometry. In addition, the effect of MK2461 on PCC-PSC interaction was investigated using PSCs prepared from pancreatic cancer tissues.RESULTSIn PSCs, PDGFRβ and MET were upregulated compared with other receptor tyrosine kinases. Conditioned medium from PSCs promoted the proliferation of PCCs, and vice versa. Moreover, MK2461 suppressed the effects of conditioned medium on PCCs and PSCs. Finally, MK2461 significantly inhibited tumor growth in mice coinjected with PCCs and PSCs.CONCLUSIONSThe PDGFRβ and MET may play a critical role in the interaction between PCCs and PSCs, which was modulated by MK2461. Therefore, MK2461 may have therapeutic potential in the treatment of pancreatic cancer.

20 May 2016·ACS Chemical BiologyQ2 · BIOLOGY

Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors

Q2 · BIOLOGY

Article

Author: Bantscheff, Marcus ; Gohlke, Bjoern ; Kuster, Bernhard ; Savitski, Mikhail M ; Helm, Dominic ; Heinzlmeir, Stephanie ; Médard, Guillaume ; Bergamini, Giovanna ; Handa, Hiroshi ; Klaeger, Susan ; Qiao, Huichao ; Preissner, Robert ; Gupta, Vipul ; Perrin, Jessica

Many protein kinases are valid drug targets in oncology because they are key components of signal transduction pathways. The number of clinical kinase inhibitors is on the rise, but these molecules often exhibit polypharmacology, potentially eliciting desired and toxic effects. Therefore, a comprehensive assessment of a compound's target space is desirable for a better understanding of its biological effects. The enzyme ferrochelatase (FECH) catalyzes the conversion of protoporphyrin IX into heme and was recently found to be an off-target of the BRAF inhibitor Vemurafenib, likely explaining the phototoxicity associated with this drug in melanoma patients. This raises the question of whether FECH binding is a more general feature of kinase inhibitors. To address this, we applied a chemical proteomics approach using kinobeads to evaluate 226 clinical kinase inhibitors for their ability to bind FECH. Surprisingly, low or submicromolar FECH binding was detected for 29 of all compounds tested and isothermal dose response measurements confirmed target engagement in cells. We also show that Vemurafenib, Linsitinib, Neratinib, and MK-2461 reduce heme levels in K562 cells, verifying that drug binding leads to a loss of FECH activity. Further biochemical and docking experiments identified the protoporphyrin pocket in FECH as one major drug binding site. Since the genetic loss of FECH activity leads to photosensitivity in humans, our data strongly suggest that FECH inhibition by kinase inhibitors is the molecular mechanism triggering photosensitivity in patients. We therefore suggest that a FECH assay should generally be part of the preclinical molecular toxicology package for the development of kinase inhibitors.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Phase 1	-	Merck Sharp & Dohme Corp.	01 Jun 2007
Solid tumor	Phase 1	JP	Merck GmbH	-
Pancreatic Cancer	Preclinical	JP	Tohoku University School of Medicine	01 Aug 2015
Advanced Malignant Solid Neoplasm	Discovery	-	Merck Sharp & Dohme Corp.	01 Jun 2007
Neoplasms	Discovery	-	Merck Sharp & Dohme Corp.	01 Jun 2007
Advanced cancer	Discovery	-	Merck Sharp & Dohme Corp.	01 Feb 2007