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Targeted Therapies
Published in Loredana G. Marcu, Iuliana Toma-Dasu, Alexandru Dasu, Claes Mercke, Radiotherapy and Clinical Radiobiology of Head and Neck Cancer, 2018
Loredana G. Marcu, Iuliana Toma-Dasu, Alexandru Dasu, Claes Mercke
The role of Src family kinases in cell signalling and morphologic transformation processes is well established. Nine members of the Src kinase family have been identified and they all belong to a family of non-receptor kinases that are involved in a number of signalling pathways controlling multiple functions such as cell adhesion, cell mobility, cell proliferation and terminal differentiation. They directly regulate several important signalling pathways including Ras/MAPK, PI3K/Akt and STAT3 (Martin 2001) and also play an important role in VEGF induced angiogenesis. The Src kinases are tyrosine kinases and participate in signal transduction in response to several stimuli, including angiogenic factors. The first defined proto-oncogene, c-Src is often overexpressed in many human malignant tumours, including HNC. Expression of activated c-Src is higher in tissues of human HNC than in normal mucosa and correlates with an invasive, poorly differentiated phenotype with more advanced nodal stage (Mandal et al. 2008).
Leukaemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2014
Following the success in the treatment of patients with CML in CP resistant/refractory or intolerant to imatinib, both dasatinib and nilotinib entered clinical trials for first-line therapy of the newly diagnosed patient in 2006.113,114 Dasatinib is a thiazole-carboxamide structurally unrelated to imatinib which binds to the ABL kinase domain (ABL KD) regardless of the conformation of the activation loop – whether open or closed. It also inhibits some of the Src family kinases. Preclinical studies showed that dasatinib was 300-fold more potent than imatinib and is active against 18 of 19 tested imatinib-resistant KD mutant subclones, with the notable exception of the T315I mutant. Nilotinib, like imatinib, acts by binding to the closed (inactive) conformation of the Abl-KD, but with a much higher affinity. Like imatinib, it inhibits the dysregulated tyrosine kinase activity of the Abl kinase by occupying the ATP-binding pocket of the oncoprotein and blocking the capacity of the enzyme to phosphorylate downstream effector molecules. In vitro studies suggest that nilotinib is approximately 30–50-fold more potent than imatinib mesylate. Nilotinib is also active in 32 of the currently 33 imatinib-resistant cell lines with mutant Abl kinases, but like imatinib and dasatinib has no activity against the Bcr-Abl1T315I mutation.
Fc Receptors
Published in Maurizio Zanetti, J. Donald Capra, The Antibodies, 1999
A first set of tyrosine kinases that are activated via FcR are src family kinases. FcɛRI aggregation was shown to activate lyn in rat basophilic leukemia (RBL) cells and yes in the mouse mastocytoma cells PT18 [219, 220]. FcγRIIIA activate lck in NK cells [221]. FcγRI activate lck, lyn and hck in U937 treated with IFNγ [222]. Lyn is associated to FcRβ in resting mast cells [220, 223] and lyn-SH2 fusion proteins could precipitate tyrosine phosphorylated FcRβ in activated RBL cells [224]. Lck associates to and phosphorylates the TCRζ subunit of FcγRIIIA in human NK cells [225, 226].
The role of N-myristoyltransferase 1 in tumour development
Published in Annals of Medicine, 2023
Hong Wang, Xin Xu, Jiayi Wang, Yongxia Qiao
The myristoyl coenzyme A analogue B13 and its derivative LCL204 were identified as small molecule inhibitors of NMT [50]. B13 prevents Src myristoylation and Src localization to the cytoplasmic membrane and attenuates Src-mediated oncogenic signalling. B13 has anti-invasive and anti-tumour effects on prostate [50] and bladder cancer cells with low toxic effects [55]. The use of these small molecule inhibitors provides a promising approach to inhibiting Src family kinase-mediated oncogenic activity [50]. The organopalladium compound dibenzylideneacetone dipalladium (Tris-DBA), is another inhibitor of human NMT synthesis, that blocks the kinase activity of NMT1 and decreases its expression. Tris-DBA shows potent anti-proliferative activity against melanoma cells by inhibiting several proliferation-related signalling pathway proteins including MAPK, Akt and STAT-3 [69]. However, the poor solubility of Tris-DBA impairs its effectiveness. Excitingly, a study synthesized Tris-DBA-Pd hyaluronic acid nanoparticles and demonstrated that this nanoparticle is an effective treatment against CD44-positive tumours such as melanoma [70]. Drug-like inhibitors IMP-366 (DDD85646) and IMP-1088 deliver complete and specific inhibition of N-myristoylation. In cancer cell lines, IMP-366 downregulates cell cycle regulatory proteins, and upregulates proteins involved in ER stress and the unfolded protein response [58]. IMP-1088, another inhibitor of both NMTs, completely inhibits N-myristoylation in a range of cell lines at low nanomolar concentrations (100 nM) [71].
Emerging therapeutic targets for idiopathic pulmonary fibrosis: preclinical progress and therapeutic implications
Published in Expert Opinion on Therapeutic Targets, 2021
Toyoshi Yanagihara, Ciaran Scallan, Kjetil Ask, Martin R. J. Kolb
Src family kinases (SKFs) are a non-receptor protein tyrosine kinase family which are activated by several profibrotic cytokines including TGF-β. They contribute to the pathogenesis of pulmonary fibrosis through several mechanisms including epithelial-mesenchymal transition, myofibroblast differentiation, and inflammatory cascades [78]. Saracatinib (AZD0530)(AstraZeneca) is a Src kinase inhibitor and has been demonstrated to block TGF-β1-induced Src kinase activation in vitro. In a bleomycin mouse model, saracitinib decreased Src kinase activation and collagen accumulation [79]. A Phase I/II double-blind, randomized, placebo-controlled trial of saracatinib (125 mg once daily) in IPF is currently enrolling. The primary objective is the assessment of safety, tolerability, pharmacokinetics, and efficacy based on change in FVC from baseline to 24-weeks (NCT04598919).
Critical redundant functions of the adapters Grb2 and Gads in platelet (hem)ITAM signaling in mice
Published in Platelets, 2020
Timo Vögtle, Ayesha A. Baig, Julia Volz, Timothy B. Duchow, Irina Pleines, Sebastian Dütting, Lars Nitschke, Stephen P. Watson, Bernhard Nieswandt
Growth-factor receptor-bound protein 2 (Grb2) and Grb2-related adapter protein downstream of Shc (Gads) are two adapter proteins that have been attributed to play roles in facilitating the formation of signaling complexes following GPVI or CLEC-2 stimulation [9,10]. In brief, ligand engagement of GPVI induces receptor clustering and activation. Src family kinases (SFK) phosphorylate the tyrosine residues of the FcRγ-chain, resulting in the recruitment and activation of Syk. This, in turn, leads to the recruitment and phosphorylation of the adapter protein Linker for activation of T cells (LAT), nucleating the assembly of the LAT signalosome. The LAT signalosome encompasses several adapters including Grb2, Gads, as well as SH2-containing leukocyte protein 76 (Slp-76), the guanine nucleotide exchange factors Vav1 and Vav3, in addition to kinases and PLCγ2. Similarly, ligand engagement of CLEC-2 leads to receptor phosphorylation of the hemITAM primarily by the kinase Syk and clustering of two CLEC-2 receptors through binding of the tandem SH2 domains in Syk, initiating a tyrosine phosphorylation cascade similar to that downstream of GPVI stimulation [11].