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Schematic illustration of ATP and peptide substrate binding to the Src kinase. Note the 3D-defined adenine binding pocket and proximate hydrophobic specificity pocket (the latter is not utilized by ATP but is exploited by inhibitors; vide infra). The N-and C-lobes of Src kinase provide extended binding sites for both ATP and peptide substrate. The divalent metal ion Mg 2+ is critical for the transfer of phosphate from ATP to the Tyr residue of the peptide substrate in the active conformation of Src kinase (relative to pTyr-416 of the activation loop).
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... the case of Src, such 3D structural properties have been also exploited by chemical genomic studies to advance novel ATP analogs modified by hydrophobic groups complementary to mutated Src kinase proteins to in- vestigate the selectivity of substrate phosphorylation in cells (69-71). Simply stated, in the case of Src ki- nase (and generally accepted for many other protein kinases), the ATP binding pocket includes a hy- drophobic specificity pocket that is not utilized by ATP itself, but may be taken advantage of by ATP binding site inhibitors functionalized by complemen- tary hydrophobic groups ( Figure 6). In this regard, Src kinase inhibitors of varying templates have been developed that target the hydrophobic specificity pocket of the ATP binding site (vide infra). ...
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... the two noncatalytic domains, the Src SH3 has been extremely recalcitrant to the discovery of small-molecule in- hibitors and, perhaps, the most sig- nificant achievement to date has been the combinatorial library-based peptidomimetic inhibitor ( Figure 15), which has been described as a potent inhibitor of Src SH3 binding, although it is not known if it pos- sesses cellular activity (91). In con- trast, the Src SH2 domain has been successfully challenged by iterative structure-based drug design strategies resulting in a series of potent nonpeptide inhibitor lig- ands, including AP21733 and AP22408 (Figures 15 and 16) (92)(93)(94). Particularly noteworthy in the context of bone-target- ing SMART drug design was AP22408, which incorporated a diphosphonoaryl-modified pTyr residue that conferred a new bi- ological property to the molecule, namely that of exhibiting affinity to bind hydroxyapatite (mineral component of bone) and subsequent osteoclast-selective activities both in vitro and in vivo (92). ...
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... the case of AP22408, the modification of the pTyr residue by a novel bone-targeted pTyr mimic (Figure 15) ad- dressed both the challenge of designing a nonhydrolyzable pTyr moiety as well as increasing the in vivo delivery of the Src SH2 inhibitor to osteoclasts in bone tissue. A 3D molecular overlay of AP22408 with both AP21733 and the cognate phosphopeptide pTyr-Glu-Glu-Ile in their binding confor- mations illustrates how beautifully the bi- cyclic nonpeptide template of AP22408 interacts with the hydrophobic surface of the Src SH2 domain as well as the favor- able interactions of its diphosphonoaryl- modified pTyr moiety at the pTyr binding site ( Figure 16). Exploitation of the bone-targeting con- cept from the above Src SH2 studies led to a significant breakthrough relative to the structure-based drug design of highly po- tent and osteoclast-selective bone-targeted Src kinase inhibitors (Figures 17 and 18) (95-97). ...
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Citations
... Human inherited blood pressure diseases are caused by mutations in WNK1, WNK4, NCC, and NKCC2, emphasizing their significance. According to recent studies, SPAK and OSR1 are interesting therapeutic candidates for the treatment of hypertension since blocking these enzymes will decrease NCC and NKCC2 activity, and hence prevent renal salt reabsorption [45][46][47]. In a variety of cancers, aurora kinases are overexpressed. ...
... According to recent human genome sequencing, protein kinases are currently recognized as a superclass of therapeutic targets with over 500 members. Table 2 can describe the classes of protein kinases [29,45]. ...
Kinase inhibitors are a significant and continuously developing division of target therapeutics. The drug discovery and improvement efforts have examined numerous attempts to target the signaling pathway of kinases. The Kinase inhibitors have been heralded as a game-changer in cancer treatment. For developing kinase inhibitors as a treatment for various non-malignant disorders like auto-immune diseases, is currently undergoing extensive research. It may be beneficial to investigate whether cell-specific kinase inhibitor administration enhances therapeutic efficacy and decreases adverse effects. The goal of the current review is to gain insight into the role of kinase inhibitors in facilitating effective target drug delivery for the treatment of various anti-inflammatory, auto-immune, and anticancer disorders. The aim of this review is also to shed light on drug discovery approaches for kinase inhibitors, their mode of action, and delivery approaches. The variation in the binding of kinases bestows different target approaches in drug design, which can be employed for designing the targeted molecules. Several target sites have been studied, exceeding the design of drugs for various diseases like cancer, Alzheimer's, rheumatoid arthritis, etc. Diverse delivery approaches have also been studied for the targeted application of kinase inhibitors.
... Src activity is regulated by two essential tyrosine residues, the first is Y527 which is dephosphorylated to convert Src enzyme from the close conformation to the open one then Y416 is autophosphorylated to catalyze Src enzyme by converting it to the active form [8]. Src is implicated in several cancers such as prostate cancers and breast cancers in addition to its role in metastasis when it has been over expressed [9]. Though both the design and synthesis of a vast number of selective inhibitors for Src enzyme, still there is an inability of finding critical chemical features of Src inhibitors [10], this leads to the importance of discovering new inhibitors by studying new molecules by molecular modeling and synthesizing them. Src has several sites to be inhibited, for example, some researchers studied the inhibition of Src by synthesis of SH 2 , SH 3 domains inhibitors while others were interested in studying ATP competitive inhibitors which bind to ATP binding site [10,11]. ...
... Though both the design and synthesis of a vast number of selective inhibitors for Src enzyme, still there is an inability of finding critical chemical features of Src inhibitors [10], this leads to the importance of discovering new inhibitors by studying new molecules by molecular modeling and synthesizing them. Src has several sites to be inhibited, for example, some researchers studied the inhibition of Src by synthesis of SH 2 , SH 3 domains inhibitors while others were interested in studying ATP competitive inhibitors which bind to ATP binding site [10,11]. Simply stated, ATP binds to the ATP binding site through several bonds, two hydrogen bonds between the purine core of ATP and the amino acids Glu339 and Met 341, in need of Mg +2 which helps to transfer the phosphate from ATP to the peptide substrate [10]. ...
... Src has several sites to be inhibited, for example, some researchers studied the inhibition of Src by synthesis of SH 2 , SH 3 domains inhibitors while others were interested in studying ATP competitive inhibitors which bind to ATP binding site [10,11]. Simply stated, ATP binds to the ATP binding site through several bonds, two hydrogen bonds between the purine core of ATP and the amino acids Glu339 and Met 341, in need of Mg +2 which helps to transfer the phosphate from ATP to the peptide substrate [10]. Moreover, the ATP site of Src includes a hydrophobic specificity pocket [10]. ...
Protein kinase, especially tyrosine kinase Src, is considered as an important target for cancer therapy such as lung, prostate and central nervous system cancers, as well as its involvement in tumor metastasis. The aim of this study was to find effective and selective inhibitors of Src protein kinase using molecular modeling study, a library of chemical compounds derived from purine and Theophylline cores was then docked within the active site of the Src enzyme. The link affinity and the attitudes of binding of the suggested compounds with the active site of the previously prepared Src enzyme were determined of these compounds. The study led to three effective and highly selective compounds on the Src enzyme; two compounds derived from the Purine core Pur46 and Pur49 and one compound derived from Theophylline core Theo21. The study was completed by chemical synthesis of Theo23 molecule.
... Over the past decade, research on the development of orally active protein kinase inhibitors has resulted in the approval of the first of these drugs for clinical use. Pharmaceutical industry is presently focusing on protein kinases as the drug targets which has led to its becoming the second major group of targets for therapy, after G-protein-coupled receptors [27]. A major breakthrough was achieved when protein kinases were identified as a key player in the development of cancer which further opened up interests in developing targeted therapies as an effective and specific way to restrict of cancer progression. ...
... A Table 1. Receptor and nonreceptor classes of tyrosine and serine/threonine kinases (Including dual specificity) [27]. ...
... The N-and C-lobes of Src kinase provide extended binding sites for both ATP and peptide substrate. The divalent metal ion Mg 2+ is critical for the transfer of phosphate from ATP to the Tyr residue of the peptide substrate in the active conformationofSrc kinase (relative to pTyr-416 of the activation loop) [27]. ...
Almost thirty percent of the protein targets currently under exploration and study constitute the protein kinases which have always attracted the pharmaceutical companies as they are easy targets for drug development. Although the kinases will remain major focus of oncology for many years to come in the development of anticancer drugs, the number of kinase inhibitors as therapeutic targets for the treatment of several other diseases which are undergoing clinical trials are exponentially increasin. In this review, we discuss very briefly the different types of protein kinases that have been used as targets for developing drugs for cancer, inflammation, autoimmune disease, heart disease andanimal diseases.
... These significant findings established the discovery of novel therapeutic strategies for preventing breast cancer metastasis to bone [22,92]. Sawyer et al. have successfully presented a smart drug design technology by using molecular selectivity (i.e., protein kinase) and cellular selectivity (i.e., bone-targeting) and obtained highly potent and osteoclast-selective bone-targeted Src kinase inhibitors [93]. It was reported that cellular selectivity design was useful to develop compounds against osteolytic bone metastasis, hypercalcemia and osteoporosis. ...
In recent years, several small molecules approved by FDA for clinical studies are promising anti-cancer agent. Among the kinases, Abelson Leukaemia (Abl), sarcoma (Src), epidermal growth factor receptor (EGFR) and vascular endotelhial growth factor receptor (VEGFR) are considered as primary molecular targets for selective inhibition and the best successful targeted therapy of tyrosine kinase inhibitors (TKIs) has been achieved in the treatment of Bcr (break point cluster)-Abl leukemia. The majority of type 1 kinase inhibitors target the active conformation of ATP binding site. In consequence of intensive studies on kinases, type 2, type 3 (allosteric) and type 4 (covalent) inhibitors have been discovered beyond the type 1 inhibitors. Although the selectivity is a major problem for type 1 inhibitors, these new type of inhibitors are promising for finding new selective compounds, which may provide other therapeutic options for cancer therapy. They may also be a solution to overcome drug resistance that remains unresolved yet. Threedimensional structural determination provides the development of specific and highly binding properties of compounds. Studying the prediction of a binding mode of inhibitors, homology model developments from kinase- ligand co-crystal structures and isosteric replacements have been used to improve binding properties of inhibitors. In this review, critical results related to the design strategies of kinase specifically targeted to Src and Bcr-Abl kinases and therapeutic potential of novel inhibitors will be evaluated. The readers will be endowed with the functional role of Src and Bcr-Abl kinases that lead inhibitor design, the structural analysis of binding modes of kinase inhibitors, the current progress in terms of therapeutic interventions and the mission of leading groups in the field.
... Therefore inhibitors of kinases and their cognate phosphatases are of considerable pharmaceutical interest for a wide variety of disease targets especially cancers [3][4][5]. Gleevac TM (Imatinib) and Iressa R (Gefitinib) developed for treatment of cancers, are tyrosine kinase inhibitors [6]. ...
Eukaryotic kinases are known to play an important role in signal transduction pathways by phosphorylating their respective substrates. Abnormal phosphorylations by these kinases have resulted in diseases. Hence inhibitors of kinases are of considerable pharmaceutical interest for a wide variety of disease targets, especially cancers. A number of reports have been published which indicate that eukaryotic-like kinases may complement two-component kinase systems in several bacteria. In Streptomyces sp. such kinases have been found to have a role in formation of aerial hyphae, spores, pigmentation & even in antibiotic production in some strains. Eukaryotic kinase inhibitors are seen to inhibit formation of aerial mycelia in Streptomyces without inhibiting vegetative mycelia. This property has been used to design an assay to screen for eukaryotic kinase inhibitors. The assay involves testing of compounds against Streptomyces 85E ATCC 55824 using agar well diffusion method. Inhibitors of kinases give rise to "bald" colonies where aerial mycelia and sporulation inhibition is seen. The assay has been standardized using known eukaryotic protein kinase inhibiting anticancer agents like AG-490, AG-1295, AG-1478, Flavopiridol and Imatinib as positive controls, at a concentration ranging from 10 μg/well to 100 μg/well. Anti-infective compounds which are not reported to inhibit eukaryotic protein kinases were used as negative controls. A number of microbial cultures have been screened for novel eukaryotic protein kinase inhibitors. Further these microbial extracts were tested in various cancer cell lines like Panel, HCT116, Calul, ACHN and H460 at a concentration of 10 μg/mL/ well. The anticancer data was seen correlating well with the Streptomyces kinase assay thus validating the assay.
... Receptor tyrosine kinases (RTKs) represent a broad class of cell surface receptors that transduce signals across the cell membrane and regulate cell proliferation, survival, differentiation and migration (Schlessinger, 2000). Activation or overexpression of most of the known RTKs has been linked to some form of cancer (Sawyer et al., 2003;Krause and Van Etten, 2005). Although the RTKs are prime targets for treatment of cancer, only a small number of therapeutics has been identified despite massive drug discovery efforts. ...
A limited number of whole-cell assays allow monitoring of receptor tyrosine kinase (RTK) activity in a signaling pathway-specific manner. We present the general use of the bioluminescence resonance energy transfer (BRET) technology to quantitatively study the pharmacology and signaling properties of the receptor tyrosine kinase (RTK) superfamily. RTK BRET-2 assays monitor, in living cells, the specific interaction between RTKs and their effector proteins, which control the activation of specific downstream signaling pathways. A total of 22 BRET assays have been established for nine RTKs derived from four subfamilies [erythroblastic leukemia viral (v-erb-b) oncogene homolog (ErbB), platelet-derived growth factor (PDGF), neurotrophic tyrosine kinase receptor (TRK), vascular endothelial growth factor (VEGF)] monitoring the interactions with five effectors (Grb2, p85, Stat5a, Shc46, PLCgamma1). These interactions are dependent on the RTK kinase activity and autophosphorylation of specific tyrosine residues in the carboxyl terminus. RTK BRET assays are highly sensitive for quantifying ligand-independent (constitutive), agonist-induced, or antagonist-inhibited RTK activity levels. We studied the signaling properties of the PDGF receptor, alpha polypeptide (PDGFRA) isoforms (V561D; D842V and delta842-845) carrying activating mutations identified in gastrointestinal stromal tumors (GIST). All three PDGFRA isoforms are fully constitutively activated, insensitive to the growth factor PDGF-BB, but show differential sensitivity of their constitutive activity to be inhibited by the inhibitor imatinib (Gleevec). Epidermal growth factor receptor (EGFR) BRET structure-function studies identify the tyrosine residues 1068, 1114, and 1148 as the main residues mediating the interaction of EGFR with the adapter protein Grb2. The BRET technology provides an assay platform to study signaling pathway-specific RTK structure-function and will facilitate drug discovery efforts for the identification of novel RTK modulators.
... The increased expression or activity correlates with the stage and metastatic potential of some neoplasia. In spite of the fact that details of several steps in SRC's oncogenic pathways still remain elusive, the knowledge of SRC activation facilitates the development of strategies to potentially inhibit SRC's pathways [133]. The rational is to design drugs that interfere with binding of either the ATP molecule or the substrate proteins: Two main approaches were established: 1) the development of SRC homologues incorporating nonhydrolyzable phosphotyrosine mimics and exhibiting molecular recognition and targeting properties. ...
Gene amplification, over-expression, and mutation of growth factors, or the receptors themselves, causes increased signaling through receptor kinases, which has been implicated in many human cancers and is associated with poor prognosis. Tumor growth has been shown to be decreased by interrupting this process of extensive growth factor-mediated signaling by directly targeting either the surface receptor or the ligand and thereby preventing cell survival and promoting apoptosis. Monoclonal antibodies have long been eyed as a potential new class of therapeutics targeting cancer and other diseases. Antibody-based therapy initially entered clinical practice when trastuzumab/Herceptin became the first clinically approved drug against an oncogene product as a well-established blocking reagent for tumors with hyperactivity of epidermal growth factor signaling pathways. In the first part of this review we explain basic terms related to the development of antibody-based drugs, give a brief historic perspective of the field, and also touch on topics such as the "humanization of antibodie" or creation of hybrid antibodies. The second part of the review gives an overview of the clinical usage of bispecific antibodies and antibodies "armed" with cytotoxic agents or enzymes. Further within this section, cancer-specific, site-specific, or signaling pathway-specific therapies are discussed in detail. Among other antibody-based therapeutic products, we discuss: Avastin (bevacizumab), CG76030, Theragyn (pemtumomab), daclizumab (Zenapax), TriAb, MDX-210, Herceptin (trastuzumab), panitumumab (ABX-EGF), mastuzimab (EMD-72000), Erbitux (certuximab, IMC225), Panorex (edrecolomab), STI571, CeaVac, Campath (alemtuizumab), Mylotarg (gemtuzumab, ozogamicin), and many others. The end of the review deliberates upon potential problems associated with cancer immunotherapy.
Src family kinases (SFKs) constitute the biggest family of non-receptor tyrosine kinases considered as therapeutic targets for cancer therapy. An aberrant expression and/or activation of the proto-oncogene c-Src kinase, which is the oldest and most studied member of the family, has long been demonstrated to play a major role in the development, growth, progression and metastasis of numerous human cancers, including colon, breast, gastric, pancreatic, lung and brain carcinomas. For these reasons, the pharmacological inhibition of c-Src activity represents an effective anticancer strategy and a few compounds targeting c-Src, together with other kinases, have been approved as drugs for cancer therapy, while others are currently undergoing preclinical studies. Nevertheless, the development of potent and selective inhibitors of c-Src aimed at properly exploiting this biological target for the treatment of cancer still represents a growing field of study. In this review, the co-crystal structures of c-Src kinase in complex with inhibitors discovered in the past two decades have been described, highlighting the key ligand–protein interactions necessary to obtain high potency and the features to be exploited for addressing selectivity and drug resistance issues, thus providing useful information for the design of new and potent c-Src kinase inhibitors.
Tomi K Sawyer received a BSc degree in Chemistry at Moorhead State University (now Minnesota State University-Moorhead) and PhD in Organic Chemistry at the University of Arizona. His research has integrated synthetic chemistry, drug design, structural biology, chemoinformatics, biochemistry, cell biology and in vivo disease models with a focus on cancer. Tomi's drug discovery track record includes contributions to clinical candidates and/or noteworthy molecular tools for several therapeutic targets, including GPCR receptors (melanocortin), aspartyl proteases (renin and HIV protease), and protein kinases (Src and Abl). He has published more than 200 scientific articles, reviews, commentaries, monographs and books. Tomi is an inventor of more than 50 issued patents and patent filings. He worked at Upjohn Company and Parke-Davis/Warner-Lambert (now both Pfizer Global Research & Development), and is currently Senior-Vice President, Drug Discovery, at ARIAD Pharmaceuticals. He is concurrently adjunct professor, Chemistry as well as Biochemistry & Molecular Biology, University of Massachusetts and also adjunct professor, Cancer Biology, at University of Massachusetts School of Medicine. Tomi has served on the highlights advisory panel of Nature Reviews Drug Discovery and the editorial advisory boards of Trends in the Pharmacological Sciences, Expert Reviews in Molecular Medicine, Expert Opinion on Investigational Drugs, Journal of Medicinal Chemistry, Chemistry and Biology, Current Medicinal Chemistry (Anti-Cancer Agents), Current Organic Synthesis, Expert Reviews in Molecular Medicine, Expert Opinion on Therapeutic Patents (Oncology), Drug Design and Discovery, Pharmaceutical Research, Molecular Biotechnology, and Biopolymers (Peptide Science). Most recently, Tomi was appointed Editor-in-Chief, Chemical Biology & Drug Design.
Src family kinases (SFKs) are a family of non-receptor tyrosine kinases (TKs) implicated in the regulation of many cellular processes. The aberrant activity of these TKs has been associated with the growth and progression of cancer. In particular, c-Src is overexpressed or hyperactivated in a variety of solid tumors and is most likely a strong promoting factor for the development of metastasis. Herein, the synthesis of new 4-aminoimidazole and 2-aminothiazole derivatives and their in vitro biological evaluation are described for their potential use as SFK inhibitors. Initially, 2-aminothiazole analogues of dasatinib and 4-aminoimidazole derivatives were synthesized and tested against the SFKs Src, Fyn, Lyn, and Yes. Five hits were identified as the most promising compounds, with Ki values in the range of 90-480 nM. A combination of molecular docking, homology modeling, and molecular dynamics were then used to investigate the possible binding mode of such compounds within the ATP binding site of the SFKs. Finally, the antiproliferative activities of the best candidates were evaluated against SH-SY5Y and K562 cell lines. Compound 3 b [2-(4-{2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl}piperazin-1-yl)ethanol] was found to be the most active inhibitor.
