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MerTK Inhibitors – Target Pipeline List 11/2018
Target: Mer tyrosine kinase, MerTK
This report provides a comprehensive overview of small molecule and antibody inhibitors of MerTK, currently in preclinical and clinical development.
MER tyrosine kinase (MerTK) has been reported to be expressed in a variety of malignancies, including leukemia, melanoma, and gastric cancer (GC). MerTKplays a pivotal role in the process of oncogenesis. MerTK is ectopically expressed in 30% to 50% of acute lymphoblastic leukemias (ALL) and more than 80% of acute myeloid leukemias (AML) and is a potential therapeutic target.
Mer is a members of the TAM (TYRO3-AXL-MER) family of receptor tyrosine kinases, which, when activated, can regulate tumor cell survival, proliferation, migration and invasion, angiogenesis, and tumor-host interactions. The MerTK pathway also drives innate immune activation. An increasing body of evidence strongly suggests that these receptors play major roles in resistance to targeted therapies and conventional cytotoxic agents.
MerTK also has been described as an immune checkpoint in macrophages, dendritic cells and other immune cells. MerTK is emerging as a promising target for cancer immunotherapy. Its expression in innate immune cells is believed to negatively regulate immune responses and genetic removal of MerTK renders mice resistant to some tumors.
The TAM family of RTKs comprises three transmembrane receptors: TYRO-3, AXL, and MER. Their extracellular domain resembles to some extent that of cell adhesion molecules and contains two immunoglobulin-like and two fibronectin type III domains, while the intracellular kinase domain mediates activation of signaling pathways.
Activation of the receptors is triggered by homodimerization following ligand binding, or ligand-independent mechanisms, such as heterodimerization with other TAM or non-TAM RTKs. Several ligands have been identified, with different affinities towards the three TAM receptors: GAS6, protein S, Tubby, Tubby-like protein 1 (TULP-1), and Galectin-3. More data are available on GAS6 and protein S since they were the first to be identified. GAS6 can bind all three receptors, whereas protein S is specific for MER and TYRO-3. The affinity of GAS6 is, however, 3- to 10-fold higher for AXL compared to MER and TYRO-3 (Schoumacher, 2017).
La Merie Publishing offers a low-cost product service providing information about active R&D projects for a given target in the format of Word tables. The Word document with the Table is delivered by e-mail within 24 hours after receipt of the confirmed order. Usually, delivery time is less than one hour if ordered during European business hours.
The Target Pipeline List in the Word table contains information about:
File: ID no. in proprietary database
Drug name: trade name, INN, drug code(s), trivial name
Target/MoA: mechanism of action
Class of compound: description of type of molecule, formulation, way and mode of administration, application device
Company: originator of molecule and licensee(s) with territories
Category: treatment modalities, i.e. antibody, protein, peptide, RNA, DNA, cells, vaccine, small molecule
Indication: medical indication evaluated in preclinical or clinical study, combination regimens
R&D Phase: from research to market with reference to indication/study
Message: last verified information about project with source and date of information and hyperlink leading to source of information
Information about R&D projects is identified and retrieved from company publications including, but not limited to, press releases, presentations, website disclosures, SEC publications, regulatory documents, scientific abstracts and full papers, patent applications. Furthermore, public and proprietary databases are used including national and regional clinical trial databases, PubMed.