Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic myeloid leukemia shown to be associated with the Ph translocation,--characterised as a t(9;22)--, joins the bcr and abl genes and leads to expression of chimeric BCR-ABL protein with enhanced tyrosine kinase (TK) activity. This increased TK activity leads to malignant transformation by interference with the control of proliferation, cellular adherence and apoptosis. The presence of this protein in every CML cells is strong evidence of its pathogenetic role. Following this observations efforts were made to develop molecularly targeted therapies for CML. The specific inhibitor of BCR-ABL TK, STI571 was developed by Brian Druker and his co-workers in 1996. STI571 (Signal Transduction Inhibitor) occupies the kinase pocket of the BCR-ABL protein, and blocks ATP binding, thereby preventing phosphorylation of any substrate. Because of promising preclinical data STI571 entered clinical trials in 1998, using an oral formulation. The reports of this trials document excellent efficacy. Patients with chronic phase after failure with interferon therapy achieved more than 90% hematologic response, usually within 4-6 weeks, and 55% major cytogenetic response. Patients with advanced disease also responded, though less durably. In phase 2 studies the drug has continued to produce impressive results. STI571 has a very favourable pharmacologic feature, with high degree of specificity for its target, and therefore low toxicity for normal tissues, it is well tolerable, side effects were minimal. STI571 opens a new era in the treatment of malignancies, it is the first targeted molecular therapy which is able to target abnormal cells without damaging normal cells, compared with traditional antineoplastic drugs.
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PMID:[Tyrosine kinase inhibitor STI571: new possibility in the treatment of chronic myeloid leukemia]. 1244 Feb 60

Akt/PKB represents a subfamily of three isoforms from the AGC serine/threonine kinase family. Amplification of Akt activity has been implicated in diseases that involve inappropriate cell survival, including a number of human malignancies. The structure of an inactive and unliganded Akt2 kinase domain reveals several features that distinguish it from other kinases. Most of the alpha helix C is disordered. The activation loop in this structure adopts a conformation that appears to sterically hinder the binding of both ATP and peptide substrate. In addition, an intramolecular disulfide bond is observed between two cysteines in the activation loop. Residues within the linker region between the N- and C-terminal lobes also contribute to the inactive conformation by partially occupying the ATP binding site.
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PMID:Crystal structure of an inactive Akt2 kinase domain. 1251 37

Because conventional chemotherapy is not specific for cancer cells leading to toxic side effects there is a need for novel agents with high grade antitumor specificity. The major prerequisite to develop such drugs is to understand the targets that these agents should attack. In recent years a number of promising new anticancer drugs have been developed which target intracellular pathways or extracellular cell molecules. The clinically most effective compounds function as tyrosine kinase inhibitors. In the past, various tyrosine kinase receptors have been identified as regulators of tumor or tumor vessel growth. Having shown their expression characteristics in different tumor entities, specific inhibitors of the ATP binding sites of these receptors or antibodies were developed and entered clinical trials. The pathognomonic role of the tyrosine kinase defines the way of action of the inhibiting drug, whereas the amount of expression in tumor tissue defines the rationale to use the inhibitor to treat a specific protein. The future will define indications for such drugs by tumor kinase profiles instead of tumor entities. Gleevec, inhibiting the BCR-ABL tyrosine kinase; Iressa, inhibiting the EGF-receptor tyrosine kinase; Herceptin, inhibiting the Her2/neu tyrosine kinase and PTK787/ZK222584, inhibiting the VEGF-receptor tyrosine kinase will be discussed as representatives of selective tyrosine kinase inhibitors whereas ZD6474 and SU6668 will be discussed as representatives of multitarget tyrosine kinase inhibitors.
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PMID:Receptor tyrosine kinases: the main targets for new anticancer therapy. 1255 64

Cancer research within the last decades elucidated signaling pathways and identified genes and proteins that lead or contribute to malignant transformation of a cell. Discovery of the Bcr-Abl oncoprotein as the molecular abnormality causing chronic myeloid leukemia (CML) paved the way for the development of a targeted anticancer therapy. The substantial activity of imatinib mesylate (STI571, Glivec) in CML and Philadelphia (Ph)-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) changed the therapeutic approach to Ph+ leukemia and rang the bell for a new era of anticancer treatment. However, when the phenomenon of relapse occurred despite continued imatinib treatment, we had to learn the lesson that imatinib can select for a resistant disease clone. If such a clone still depends on Bcr-Abl, it either carries a BCR-ABL point mutation that prevents binding of the drug or expresses the fusion protein at high levels. Alternatively, leukemia cells that harbor secondary genetic alterations resulting in Bcr-Abl-independent proliferation are selected for their growth advantage in the presence of imatinib. Point mutations in the BCR-ABL kinase domain prevent binding of imatinib but still allow binding of ATP, thus retaining Bcr-Abl kinase activity. Mutated BCR-ABL is frequently detected in cases of imatinib-resistant Ph+ leukemia and therefore represents the main challenge for the investigation of alternative strategies to either overcome resistance or to prevent the emergence of a resistant leukemic clone.
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PMID:Resistance of Philadelphia-chromosome positive leukemia towards the kinase inhibitor imatinib (STI571, Glivec): a targeted oncoprotein strikes back. 1275 Jun 93

CSK family contains two protein tyrosine kinases: Csk (C-terminal Src kinase) and Chk (Csk homologous kinase). They are responsible for phosphorylating Src family protein tyrosine kinases on a C-terminal Tyr (Tyr527) and negatively regulating their activities. However, Chk and Csk have different expression patterns, mechanisms of regulation, and different biological functions, and appear to play different roles in the development of breast cancer. To obtain pure human Chk for biochemical characterization, its coding region was amplified by polymerase chain reaction and expressed as a fusion protein with glutathione S-transferase in Escherichia coli. The enzyme was highly expressed but unusually prone to proteolytic degradation during purification. Expression of the enzyme as a dual fusion protein with glutathione S-transferase on N-terminus and streptag, a 10 amino acid peptide, on C-terminus allowed purification of the full-length fusion protein. The purified enzyme was able to phosphorylate and inactivate Src. Chk (no inhibition up to 18.5 microM) and Csk (IC(50)= 1 microM) were differentially inhibited by PP2, probably due to the size difference of one residue (Thr265 in Csk versus Met304 in Chk) in the ATP-binding domain. The expression, purification, and initial characterizations of Chk provided an important step toward full characterization of Chk and Csk, two important enzymes in cellular regulation.
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PMID:Expression, purification, and biochemical characterization of Chk, a soluble protein tyrosine kinase. 1276 3

The mutation of well behaved enzymes in order to simulate less manageable cognates is the obvious approach to study specific features of the recalcitrant target. Accordingly, the prototypical protein kinase PKA serves as a model for many kinases, including the closely related PKB, an AGC family protein kinase now implicated as oncogenic in several cancers. Two residues that differ between the alpha isoforms of PKA and PKB at the adenine-binding site generate differing shapes of the binding surface and are likely to play a role in ligand selectivity. As the corresponding mutations in PKA, V123A would enlarge the adenine pocket, while L173M would alter both the shape and its electronic character of the adenine-binding surface. We have determined the structures of the corresponding double mutant (PKAB2: PKAalpha V123A, L173M) in apo and MgATP-bound states, and observed structural alterations of a residue not previously involved in ATP-binding interactions: the side-chain of Q181, which in native PKA points away from the ATP-binding site, adopts in apo double mutant protein a new rotamer conformation, which places the polar groups at the hinge region in the ATP pocket. MgATP binding forces Q181 back to the position seen in native PKA. The crystal structure shows that ATP binding geometry is identical with that in native PKA but in this case was determined under conditions with only a single Mg ion ligand. Surface plasmon resonance spectroscopy studies show that significant energy is required for this ligand-induced transition. An additional PKA/PKB mutation, Q181K, corrects the defect, as shown both by the crystal structure of triple mutant PKAB3 (PKAalpha V123A, L173M, Q181K) and by surface plasmon resonance spectroscopy binding studies with ATP and three isoquinoline inhibitors. Thus, the triple mutant serves well as an easily crystallizable model for PKB inhibitor interactions. Further, the phenomenon of Q181 shows how crystallographic analysis should accompany mutant studies to monitor possible spurious structural effects.
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PMID:Mutants of protein kinase A that mimic the ATP-binding site of protein kinase B (AKT). 1279 91

Growth factor binding events to receptor tyrosine kinases result in activation of phosphatidylinositol 3-kinase (PI3K), and activated PI3K generates the membrane-bound second messengers phosphatidylinositol 3,4-diphosphate [PI(3,4)P2] and PI(3,4,5)P3, which mediate membrane translocation of the phosphoinositide-dependent kinase-1 (PDK1) and protein kinase B (PKB, also known as Akt). In addition to the kinase domain, PDK1 and PKB contain a pleckstrin homology (PH) domain that binds to the second messenger, resulting in the phosphorylation and activation of PKB by PDK1. Recent evidence indicates that constitutive activation of PKB contributes to cancer progression by promoting proliferation and increased cell survival. The indicating of PDK1 and PKB as primary targets for discovery of anticancer drugs, together with the observations that both PDK1 and PKB contain small-molecule regulatory binding sites that may be in proximity to the kinase active site, make PDK1 and PKB ideal targets for the development of new strategies to structure-based drug design. While X-ray structures have been reported for the kinase domains of PDK1 and PKB, no suitable crystals have been obtained for either PDK1 or PKB with their PH domains intact. In this regard, a novel structure-based strategy is proposed, which utilizes segmental isotopic labeling of the PH domain in combination with site-directed spin labeling of the kinase active site. Then, long-range distance restraints between the 15N-labeled backbone amide groups of the PH domain and the unpaired electron of the active site spin label can be determined from magnetic resonance studies of the enhancement effect that the paramagnetic spin label has on the nuclear relaxation rates of the amide protons. The determination of the structure and position of the PH domain with respect to the known X-ray structure of the kinase active site could be useful in the rational design of potent and selective inhibitors of PDK1 and PKB by 'linking' the free energies of binding of substrate (ATP) analogs with analogs of the inositol polar head group of the phospholipid second messenger. The combined use of X-ray crystallography, segmental isotopic and spin labeling, and magnetic resonance studies can be further extended to the study of other dynamic multidomain proteins and targets for structure-based drug design.
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PMID:PDK1 and PKB/Akt: ideal targets for development of new strategies to structure-based drug design. 1282 87

Chronic myeloid leukemia (CML) is characterized by the Philadelphia translocation that fuses BCR sequences from chromosome 22 upstream of the ABL gene on chromosome 9. The chimerical Bcr-Abl protein expressed by CML cells has constitutive tyrosine kinase activity, which is essential for the pathogenesis of the disease. Imatinib, an ATP-competitive selective inhibitor of Bcr-Abl, has unprecedented efficacy for the treatment of CML. Most patients with early stage disease achieve durable complete hematological and complete cytogenetic remissions, with minimal toxicity. In contrast, responses are less stable in patients with advanced CML. This review highlights the pathogenesis of CML, its clinical features, and the development of imatinib as a specific molecularly targeted therapy. Aspects of disease monitoring and side effects are covered as well as resistance to imatinib and strategies to overcome resistance, such as alternative signal transduction inhibitors and drug combinations. Perspectives for further development are also discussed.
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PMID:Specific targeted therapy of chronic myelogenous leukemia with imatinib. 1286 62

Imatinib mesylate (STI571) is a major therapeutic advance for the management of chronic myeloid leukaemia (CML), however, a proportion of patients are refractory to it, particularly those in more advanced phases of CML. Different mechanisms of resistance to imatinib are suggested, including point mutations within ABL-kinase domains. A point mutation leading to substitution at the ATP binding site of ABL-kinase and insensitivity to imatinib was detected in our patient treated with imatinib, who progressed to blast crisis. Additionally, clonal evolution could lead to BCR-ABL-independent proliferation. Early detection of ABL-kinase mutation could predict the progression of CML treated with imatinib.
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PMID:ABL-kinase domain point mutation as a cause of imatinib (STI571) resistance in CML patient who progress to myeloid blast crisis. 1292 56

Imatinib mesylate is a 2-phenylaminopyrimidine tyrosine kinase inhibitor with specific activity for ABL, platelet-derived growth factor receptor, and c-kit receptor. The pharmacological basis of this interaction has been elucidated by crystallographic studies. Imatinib mesylate binds to the amino acids of the BCR-ABL tyrosine kinase ATP binding site and stabilizes the inactive, non-ATP-binding form of BCR-ABL, thereby preventing tyrosine autophosphorylation, and in turn, phosphorylation of its substrates. This process ultimately results in a "switch-off" of the downstream signaling pathways that promote leukemogenesis. Despite high rates of hematologic and cytogenetic responses to imatinib therapy, the emergence of resistance to imatinib has been recognized as a major problem in the treatment of Ph-positive leukemia. Considerable progress has been made in developing therapeutic agents that are effective against molecular targets specifically expressed in CML cells. It is important to emphasize that BCR-ABL is the ideal target for therapy even at relapse; at least one general mechanism of resistance involves maintenance of an active BCR-ABL kinase inside leukemic cells. It is also notable that the high frequency of BCR-ABL mutations and amplifications represents the high degree of heterogeneity in patients with advanced CML, in whom multiple leukemic clones may exist. For these reasons, a single inhibitor is unlikely to be able to block all mutants described so far.
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PMID:[Molecular-target therapy of Ph-positive leukemia by imatinib (tyrosine kinase inhibitor)]. 1293 59


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