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Protein Phosphorylation
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
The Fyn tyrosine kinase is, in concert with the Lck kinase, a signal transduction element of the T-cell antigen receptor complex.243 The Fyn kinase is activated following T-cell antigen receptor crosslinking.244 Both Fyn and Lck are involved in phospholipase C-γ phosphorylation and activation, as well as in protein kinase C activation and intracellular Ca2+ mobilization. The CDC45 phosphotyrosine phosphatase regulates Fyn, but not Lck, tyrosine kinase activity in HPB-ALL T cells.245 In the YT human natural killer-like cell line, Fyn is physically associated with the low-affinity Fc receptor for IgE.246 This receptor is identical to the lymphocyte differentiation antigen CD23 and is involved not only in the regulation of IgE production but also in the activation or transformation of lymphoid cells, particularly of B-cell lineage. The Fyn tyrosine kinase is also involved in the mechanism of action of IL-7.247 The IL-7 receptor may function by recruiting the Fyn protein through a segment of its cytoplasmic tail, which may lead to the activation of PI 3-kinase, an enzyme involved in the regulation of cell proliferation.
Current Inhibitors of Dengue Virus
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
J. Jonathan Harburn, G. Stuart Cockerill
A number of molecules have also been identified as either targeting host proteins, or essentially of unknown mechanisms. Known kinase inhibitors are prominent in this group of inhibitors, with inhibitors of the c-Src protooncogene and Bruton’s tyrosine (BTK) at the forefront. Src family kinase inhibitors with activity against DENV were described in 2007 (Chu and Yang 2007). Both Dasatinib 8-1 and Saracatinib 8-2 have been identified with moderate levels of activity against DENV2 (Figure 8). The depletion of major kinases associated with these inhibitors utilising RNAi was used to identify the Src family kinase Fyn as the major mediator of the anti-viral effect (de Wispelaere et al. 2013). A study based upon utilising Src kinase inhibitors as the starting point was, after looking at a number of scaffolds, able to identify purine as 8-3 as a dual inhibitor of both the kinases Src/Fyn as well as being the first example of an inhibitor of a key NS5-NS3 interaction (Vincetti et al. 2015). Mutagenesis studies, involving amino acid residues contained within an allosteric pocket on the polymerase, had proposed this pocket as a key inhibitor binding pocket, disruption of this pocket being crucial to the inhibition of the initiation of RNA synthesis and the formation of a functional polymerase-helix complex. A design process utilising virtual screening of an in-house library was supported by an Alphascreen NS5-NS3 interaction assay to evaluate hit compounds. Induced fit docking was further used to confirm the binding mode for 8-3. Anti-viral potency at micromolar level was achieved with a good selectivity index.
Role of Engineered Proteins as Therapeutic Formulations
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Khushboo Gulati, Krishna Mohan Poluri
Fynomers are the protein scaffolds designed based on the SH3 domain of Fyn enzyme. Fyn enzyme is a tyrosine kinase (belongs to Src family) containing 5 anti-parallel β-strands connected by two loops (Musacchio et al., 1992; Musacchio et al., 1994). Src domain involves in interaction with many proteins associated with cell signaling, cytoskeleton structures, and membrane receptors. Hence, efforts are being made to add diversity to the fynomers by mutagenesis in the two flexible loops. Fyn SH3 domains are also devoid of cysteine residues, hence do not form disulfide bonds and therefore can be expressed efficiently in bacteria. Additional features of higher stability and their occurrence in monomeric form makes fynomers potent therapeutic scaffolds. Fynomers known as 2C1, specific to human IL-17A were designed. They bind to IL-17A with nano-molar affinity. Continuous efforts are being made to fuse the fynomers to antibodies to make them bi-specific or tri-specific or increase their binding affinity to the target protein. 2C1 was fused to the Fc region of antibody using a four amino acid linker. The fynomer-Fc fusion had shown pico-molar binding affinity to IL-17A. Hence, these fusion constructs of fynomers with 100 fold improvement in inhibition of IL-17A, represent the ideal drug candidates for treating IL-17A mediated diseases (psoriasis, psoriatic arthritis and rheumatoid arthritis, etc.) (Silacci et al., 2014). Bispecific FynomAb COVA208 has been designed that reduced the levels of HER2, HER3, and EGFR and thereby showed strong inhibitory action on the downstream signaling of HER2 pathway (Brack et al., 2014).
Investigational therapies in phase II clinical trials for the treatment of soft tissue sarcoma
Published in Expert Opinion on Investigational Drugs, 2019
Juan Martin-Liberal, Ezequiel Pérez, Xavier García Del Muro
Dasatinib is a multi-tyrosine kinase inhibitor of BCR-ABL, SRC family kinases (SRC, LCK, YES, FYN), KIT, platelet-derived growth factor receptor (PDGFR)-α, PDGFR-β and ephrin receptor kinase [29]. SRC has been reported to be overexpressed in certain sarcoma subtypes such as leiomyosarcoma and to have a role in the malignant phenotype of chondrosarcoma and synovial sarcoma through the activation of its pathway [30–32]. Therefore, treating STS patients with dasatinib is a sensible approach. This strategy was evaluated in a phase II trial which enrolled 200 previously treated advanced sarcoma patients into 7 cohorts according to different aggressive histologic subtypes: leiomyosarcoma, liposarcoma, undifferentiated pleomorfic sarcoma (UPS), malignant peripheral nerve sheath tumor (MPNST), osteosarcoma, Ewing sarcoma and rhabdomyosarcoma. The primary endpoint was clinical benefit rate (CBR), defined as complete response (CR) or PR within 6 months or SD duration of at least 6 months. The leiomyosarcoma and the UPS cohorts were the only two in which dasatinib showed some clinical benefit, with a probability of CBR ≥ 25% in the leiomyosarcoma and the UPS cohorts of 0.008 and 0.10, respectively. The longest progression-free survival (PFS) was observed in the leiomyosarcoma cohort but it was only of 2.2 months. The authors conclude that dasatinib has modest activity in UPS and no activity in other sarcoma subtypes [33].
Spontaneous subdural hematoma in a patient with Philadelphia chromosome-positive acute lymphoblastic leukemia with normal platelet count after dasatinib treatment
Published in Platelets, 2015
Moaath K. Mustafa Ali, Marwa M. Sabha, Kamal H. Al-Rabi
Dasatinib, which is a second generation BCR-ABL tyrosine kinase inhibitor (TKI), has been approved for the treatment of Philadelphia chromosome (Ph)-positive malignancies such as acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML) [1, 2]. Dasatinib targets most imatinib-resistant BCR-ABL mutations by distinctly binding to active and inactive ABL-kinase. This inhibition blocks proliferation of leukemia cells. Dasatinib has also been shown to inhibit SRC family (including SRC, LKC, YES, FYN); c-KIT, EPHA2 and platelet derived growth factor receptor (PDGFRβ) [3, 4]. In vitro, dasatinib has 325-fold greater potency than imatinib mesylate (IM) for inhibiting BCR-ABL [4]. Several adverse reactions have been encountered with dasatinib use, including: headache, fatigue, skin rash, diarrhea, abdominal pain, nausea, vomiting, pleural effusion, myelosuppression and hemorrhage. Hemorrhage has been reported in 9–40% of patients using dasatinib [5, 6]. Bleeding can be: gastrointestinal, genitourinary, soft tissue hematoma and central nervous system (CNS) bleeding. In this case, we describe a patient who developed spontaneous SDH after dasatinib treatment. The patient did not have any risk factors for SDH, making dasatinib induced-platelet dysfunction the most likely cause.
Fyn gene silencing reduces oligodendrocytes apoptosis through inhibiting ERK1/2 phosphorylation in epilepsy
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2020
Xinming Luo, Zhengyu Li, Jing Zhao, Yan Deng, Yuqin Zhong, Ming Zhang
Fyn is a member of the Src family of non-receptor protein tyrosine kinases. Fyn is highly expressed in OLs and plays an important role in the initial stage of myelin formation [7,8]. A recent report reveals that myelin thinning in Fyn deficient mice is 40–50% [9]. Fyn has no extracellular and transmembrane regions. It is free in the cytoplasm or connects to the membrane by acyl groups at the amino terminal. When cells are activated by external signals related to their differentiation and development, phosphorylation of tyrosine residues of target proteins enables Fyn to transmit information within cells, consequently activating downstream signals [10].