The following theories elaborated for the description of IR spectra of secondary amide crystals may be divided into two groups: 1. Theories of the first group tried to explain the mechanism of the generation of the CdO group stretching vibration bands in the IR spectra of peptides. The subsequent versions of Davydovs Solution theory belong to this group. In these models excitations were obtained as polaronic type solutions of a Hamiltonian describing the interaction of the amide I vibration quanta with low frequency lattice 40_44 2. Theories of the other group comprise models focused on the generation mechanisms of the fine structure pattern of the N_H proton stretching vibration bands in IR spectra of hydrogen bonded amide crystals.

A wide spectrum of theories was proposed from the models assuming Fermi resonance mechanism involving the proton stretching vibrations and some other vibrations of the hydrogen bonded molecule to theories assuming vibrational exciton N_H band fine structure pattern could not be explained in terms of the formalism of the Fermi resonance Cell Cycle mechanism. On studying the temperature efects in polarized IR spectra of acetanilide and acetanilide 8d crystals and on the basis of the femtosecond infrared pump_probe experiments, they proposed the so called self trapping theory. In this model an exciton_ phonon coupling plays an essential role that leads to the vibra tional self trapping state. Within this theory, the lower frequency branch of the band is generated by the transition to a hypothetical metastable excited state of the proton stretching vibrations in the hydrogen bond lattice of the crystal, which anharmonically couple with the low frequency N 3 3 3 O hydrogen bridge stretching vibrations.

As the result of such a coupling, the absorption spectra in the band frequency range exhibit Apoptosis shapes qualitatively resembling typical Franck_Condon type progressions, composed of one vibrational excitation quantum CdO modes. Edller and Hamm noticed that the generation of the several quanta of phonon excitation. This theory has been Figure 4. Impact of temperature on the polarized spectra of the most intense components of the PAM crystal: the ac plane case, the ab crystalline face case. proposed recently and is highly intuitive as well as being only of a qualitative character.

The model of the metastable state within the self trapping theory is totally abstracted from the state of art in the quantitative theories of the IR spectra of the hydrogen bond dimers and hydrogen bonded crystals. The authors of the self trapping theory have not considered the H/D isotopic CFTR efects in the IR spectra of the hydrogen bond of amide crystals. This N_H band shapes characterizing crystals of diverse secondary amide systems. Moreover, to the authors knowledge no monograph dealing with the quantitative interpretation of IR spectra of PAM crystals has been published so far. 3. 2. Initial Studies of Vibrational Spectra of PAM Crystals. The N_H band in the IR spectra of PAM crystal consists of several intense, well resolved spectral lines. In Figure3 IR spectra of polycrystalline samples of the compound measured at 293K and 77 K are presented.

Also the Raman spectrum is shown to identify the lines attributed to the C_H bond stretching vibrations. The C_H bond stretching vibration lines CFTR facilitate identification of crystal faces developed during crystallization from melt. In the spectra of the PAM crystal the N_H band shift toward the lower frequencies, accompanying the formation of the hydrogen bond, is ca. equal to 250 cm. This fact indicates that hydrogen bonds are relatively strong. An identical conclusion can be drawn from the geometry of hydrogen bonds in the crystal approach also does not explain the diferences. 3. 1. Temperature Effects in IR Spectra of PAM. In Figure 4 the temperature effect in the spectra of the two forms of PAM crystals is shown. From these spectra it results that on a N_H band remains almost unchanged.

In these circumstances, the intensity of the band lower frequency branch increases. The temperature efects in the crystal spectra seem to be very complex. This efect probably is connected with the averaging of the bent structure of the hydrogen bridges toward the HSP axial symmetry at growing temperatures. On the other hand, the equilibrium geometry of the hydrogen bonds is temperature dependent. This fact poses a problem for the theoretical models describing spectra of crystals with hydrogen bonds. 3. 3. Linear Dichroic Effects in the Spectra. Polarized IR spectra of the hydrogen bond in PAM crystals measured in the frequency range of the band for two individual crystal forms, each having developed another crystal plane, are shown in Figure 5. Spectra of the two different crystal forms differ from one another by the intensities of their lower frequency band branches and by relative intensities of the C_H bond stretching vibration lines. Although in the spectra of the two crystal forms some splitting efects accompanied by slight local linear dichroic efects can be temperature decrease the higher frequency branch of the N_H Figure 7.

Calein. Diamagnetic metal ions and Zn2 Ga3 were used as probes for Fe2 and Fe3, respectively used as the iron complexes not detectable by NMR. All studies were performed in an L Solvents conducted 50/50 DMSO TrisHCl d6/D2O. 1H NMR assignments for advanced baicalein were reported on by Lim and colleagues. GSK461364 The 1H NMR spectra of the titration of 5 mM Zn2 with baicalein was shown. 5th Were not included as Zn2 Changes observed for most of the peaks baicalein, but the H8 protons experienced a large e Ver Change by downfield. The summit of protons H3 also slightly downfield. to 1 molar equivalent. Zn2 added, a precipitate thus lower Signalintensit Was observed t. Ver these Change indicates that the NMR binding site in the N eh The metal proton H8, i. E. O6 O7 website and cycle A.
This binding site was best performed by Similar experiments with baicalin, the gel Nde O7 has blocked by a glucose unit CONFIRMS. No ENMD-2076 Ver Change was observed by NMR after addition of Zn2 In baicalin and best Firmed that the website is authentic O7 for Zn2 essential. Titration with Ga3 baicalein showed anything similar 1H-NMR chemical shifts relative to those with Zn2, i observed. s H3 was a slight shift to lower field, w during H8 was a big e Ver downfield change, suggesting that Ga3 binds the same site as Zn2. However, since several Ga3 added appeared new NMR peaks,. The formation of several species No attempt was made to identify these species. Proof of our NMR investigations k Can we eventually found that the metal between the hydroxyl carbons 6 and 7 in complex baicalein Zn or Ga.
Because of Hnlichen properties coordination of Fe2 and Zn2 and Fe3 and Ga3, and under into account the results of studies on MS UV / Vis and ESI, it can suggested that both Fe2 and Fe3 bind baicalein on the same gel nde Zn2or Ga3 as do i. e, O6 and O7 site on the ring A. Figure 7 shows the proposed structure for the species Fe2 baicalein. The inhibition of the Fenton chemistry baicalein and baicalin deoxyribose degradation by two tests were conducted to determine the capability F Baicalin and baicalein, the formation of hydroxyl radicals by the Fenton reaction found Promotes inhibit evaluated. 8A shows the absorbance at 532 nm of the complex TBA malonaldehyde dependence Dependence.
On the concentration in the absence of Fe2 flavones, in the presence of 10 M baicalin, baicalein and 10 million It is clear that baicalein can completely Constantly inhibit Fenton-induced radicals caused Sch The even at concentrations up to 20 h at M. Fe2 Heren concentrations up to 50 M Fe2, curve slightly increased, but the inhibition is always still important. Under the same conditions can baicalin partially protect the deoxyribose molecule two Fenton Sch The by free radicals. As of the NMR study, baicalin not bind iron showed strong protection against radicals is probably part baicalin its free-radical singer-activity t. Kl to the mechanism by which baicalein Fenton-induced radicals Sch To inhibit i can Ren. e whether chelation or free-radical singer, Fe2 EDTA was used to rdern Fenton chemistry to f. Since EDTA can have a binding constant of iron by several Gr Enordnungen hours ago Than that of baicalein as baicalein-radical singer act in the Fe EDTA. 8B s

95% of patients display a reciprocal translocation between chromosomes 9 and 22. The resulting Philadelphia chromosome abnormality yields a fusion gene encoding a constitutively active Bcr Abl tyrosine kinase that is considered essential for the pathophysiology of CML. 1, 2 In the United States, about 5000 people are diagnosed with CML each year.3 Historically, the  5 year survival rate for Ecdysone patients with CML in chronic phase was approximately 40%.4 Since the introduction in 2001 of the first specific Bcr Abl tyrosine kinase inhibitor, imatinib mesylate, the estimated 5 to 7 year survival rates for newly diagnosed patients with CML CP have increased to over 90%.5 8 As patients with CML live longer, prevalence of the disease is expected to increase over the coming years.
The success of imatinib demonstrates that specific inhibition of Bcr Abl kinase has clinical benefits in the treatment of CML. However, based on the findings of a 5 year follow up assessment, imatinib resistance occurs at a rate of approximately 4% per year.7, 8 Resistance is believed to be due to 3 main mechanisms: increased expression of Bcr Abl, Bcr MK-2206 Abl mutations, and the development of Bcr Abl independent resistance pathways, such as Lyn kinase activation.6, 9, 10 In patients with Ph positive acute lymphocytic leukemia, or those with CML in accelerated phase or blastic phase, imatinib treatment often fails to achieve high rates of complete cytogenetic response, these patients frequently develop resistance to therapy and relapse.
In 20% to 55% of such patients, treatment resistance can be attributed to the emergence of clones with mutant forms of Bcr Abl, which exhibit a decreased sensitivity to imatinib. More than 60 mutant forms of Bcr Abl have been detected,11 14 the most common of which are E255K, T315I, and M351T. Mutants have varying degrees of imatinib resistance,15 17 and thus more potent Bcr Abl inhibitors or dual Abl/Lyn inhibitors may improve treatment results. INNO 406, a dual Abl/Lyn tyrosine kinase inhibitor, may be an effective treatment for certain leukemias. INNO 406, was developed to overcome imatinib resistance.11, 12 Unlike other second generation TKIs, INNO 406 demonstrates specific Lyn kinase activity with no or limited activity against other Src family member kinases. Numerous Bcr Abl kinase domain mutations are sensitive to INNO 406 in vitro, including the F317L and F317V mutations.
INNO 406 is 25 to 55 times more potent than imatinib against Bcr Abl positive leukemic cell lines K562 and KU812 and against BaF3 cells overexpressing unmutated Bcr Abl. Autophosphorylation of unmutated Bcr Abl is also more potently inhibited by INNO 406 than by imatinib. In vivo, INNO 406 is at least 10 times more potent than imatinib.18, 19 Chemically, INNO 406 is a 2 phenlaminopyrimidine with structural resemblance to both imatinib and nilotinib. The molecular structure of INNO 406 is shown in Figure 1. This phase 1, open label, nonrandomized dose escalation study was conducted at 6 international sites from July 17, 2006, to November 28, 2007, to determine the safety, tolerability, pharmacokinetic profile, and clinical activity of INNO 406 administered orally daily in adult patients with Ph positive CML or ALL post imatinib resistance or intolerance. METHODS Patients

Ted tested the growth inhibitory effects of kinase inhibitor sorafenib in eight different multiple cultures metastatic melanoma cell lines. Moreover k Nnten Combined with sorafenib Lonafarnib induce apoptosis and to abolish the invasive potential of melanoma cells. Besides RTI have developed pharmacological CYT997 agents directly to the RAS and also inhibit evlauated in pr Clinical trials and in clinical studies of melanoma. BMS 214,662 and 778,123 L, non-peptidic inhibitors of RAS H and K were each tested against melanoma. In a phase I study in patients with solid tumors, the oral 214662 BMS experienced doselimiting toxicity t manifested by nausea, diarrhea, vomiting, Bauchkr Cramps, loss of appetite, fatigue and fever. Was 23 patients, with the exception of 1 disease.
Although the pharmacokinetics of the drug was favorable oral bioavailability in oral form proposed then abandoned because of gastrointestinal intolerance. In another phase I study was initially ITF2357 BMS 214662 Highest administered in 30 patients over a period of 1 hour per week. A minor response in a patient was refractory to chemotherapy Ren reported breast cancer. The 778,123 was also evaluated clinically by a continuous infusion for 5 days the agent alone or in combination with radiotherapy and paclitaxel for the treatment of NSCLC, and carcinoma of the head and neck. Despite a good clinical response studies for lack of evidence relates to the heart sank, manifested as a Pub EXTENSIONS of the QTc interval. Unfortunately, these two compounds were ineffective in melanoma, like most port-RAS and N is not H or K-RAS mutations.
RAS inhibitor tested in combination with radiation or cytotoxic drugs in pr Clinical and clinical trials, and also ineffective. Thus, therapeutic targeting RAS in melanoma cells is relatively ineffective, suggesting that other points of the MAPK pathway may be the most promising targets. 2.3. Target for Melanoma B RAF RAF B is inhibiting one of three members of the RAF RAF family, the A, B and RAF CRAF lt contains, And is a downstream effector of RAS. The three isoforms of RAF S ugetieren While at the same three conserved regions are also significant differences in the variable sequences. CR1 contains Lt one Bindungsdom Ne and a cysteine-rich RAS Cathedral ne. The CR2 Cathedral ne Contains Lt serine and threonine residues, plays an r In regulating the activity B RAF t on phosphorylation.
CR3 contains Lt the kinase Dom ne and phosphorylation of key sites, the enzyme activity Regulate t. The activation of normal proteins mutated RAF is not a complex process, which can include a number of events including membrane translocation, dimerization protein tyrosine phosphorylation by SRC family, the dissociation of protein kinase inhibitors and RAF, together with RAF scaffoldingB the gene in the MAPK cascade in melanomas mutated, wherein. 60% of advanced tumors, the constitutively active mutant protein Activating BRAF mutations are acquired, somatic and zygotic contribution events are not inherited in families. W While more than 65 different mutations in more than 30 codons RAF B, a single base are T missense substitution of a present that changed Valine for glutamic Acid

Esistance to AZD1480 therapy in HL patients. The fact that AZD1480 synergized AS-252424  characterized by AZD1480 induced ERK hyperactivation strongly supports the hypothesis that ERK hyperactivation may be an important mechanism of resistance to the JAK inhibition in HL. In this study, we show that higher concentrations of AZD1480 inhibited Aurora kinases and induced G2/M cell cycle arrest and cell death in all HL cell lines, irrespective of JAK/STAT pathway status. Aurora A has a crucial role in mitotic bipolar spindle formation and localizes to centrosomes at the proximal mitotic spindle, whereas Aurora B localizes to kinetochores, phosphorylates histone H3 at Ser10, and has a role in chromosome alignment and cytokinesis.
35 Inhibition of Aurora kinases promotes G2/M arrest and apoptosis in multiple human cancers including lymphoid malignancies,36 38 but no data are available, which suggest a role of Aurora kinases in Hodgkin lymphomagenesis. We found that Aurora A and B kinases were overexpressed in the four HL cell lines compared with PBMCs from healthy donors. AZD1480 promoted Bafetinib a dose dependent inhibition of Aurora A autophosphorylation at Thr288 in all the four HL cell lines. We observed a tight correlation between the dose dependent inhibition of Aurora A and the changes observed in cell cycle fraction and apoptosis in HL cells. A dose dependent inhibition of histone H3 phosphorylation at ser 10 was detected in two cell lines, suggesting that high doses of AZD1480 may also inhibit Aurora B in these cell lines.
Due to the fact that Reed Sternberg cells account for less than 5% of the entire tumor mass, being very rare in the affected lymph nodes, we were not able to microdissect viable primary HRS cells from patients, lymph nodes to perform in vitro viability and functional assays. Figure 6 Model for AZD1480 activity in HL cells. A model showing the dual, dose dependent mechanism of action of AZD1480 in HL cells. At low doses, AZD1480 inhibits the JAK/STAT pathway, showing predominantly immunoregulatory effects. At high doses, AZD1480 also inhibits the Aurora kinases, promoting G2/M arrest and apoptosis in HL cells. Activity of AZD1480 in Hodgkin lymphoma E Derenzini et al However, our data clearly demonstrate that AZD1480 inhibits JAK/STAT activation in cultured HL cells at submicromolar concentrations, by blocking the function of JAKs and determining immunomodulatory effects.
Moreover, the two cell lines, which showed MAP kinase hyperactivation following treatment with AZD1480, were resistant to the drug at concentrations clearly able to inhibit STATs phosphorylation. The fact that different MEK inhibitors synergized with AZD1480 in these two resistant cell lines, suggest that this negative feedback loop activating MAP kinases could be an important mechanism of resistance to AZD1480. In summary, our results provide preclinical rationale for further clinical investigation of AZD1480 in HL and provide molecular rationale for incorporating biomarker studies according to the primary target inhibition. Furthermore, our data demonstrate the importance of evaluating the in vivo effect of small molecule inhibitors on secondary signaling pathways that may mediate resistance to therapy and pr

Since both vaccines have previously evoked high Bafetinib titers of IgG antibodies against alginate, LPS, and toxin A in healthy volunteers, an immunologic interference may have occurred in the rats, resulting in an antagonistic antibody response. The reason for this is unclear but may be related to immunosuppressive effects of some P. aeruginosa LPSs. Toxin A is known to be an important virulence factor, and when it is secreted by P. aeruginosa, it has been shown to be associated with severe bronchial inflammation and parenchymal changes. Anti toxin A antibodies could be demonstrated in all rats immunized with toxin A conjugated vaccines. However, toxin A did not significantly improve the lung abnormalities when compared with the sterile saline controls.
The protective capability of the LPS vaccine used in the present study is not completely in accordance with the findings of Pennington et al. We found that rats immunized with LPS containing P. aeruginosa sonicate had more severe lung damage and reduced Epothilone B bacterial elimination but had higher antibody titers directed against most of the antigens used in the ELISAs. The severe abnormalities and reduced clearance could be due to hypersensitivity reactions, e. g, immune complexes, of which there was no evidence in the study performed by Pennington et al. The more severe macroscopic abnormalities observed among our immunized rats fit well with the observations of Langford and Hiller, who found that vaccination of noninfected CF patients with a polyvalent P. aeruginosa vaccine induced more rapid deterioration than that found in nonvaccinated controls.
The accelerated course of the disease in vaccinated patients may also be explained by hypersensitivity reactions, e. g, immune complex mediated lung tissue damage, which occurs during chronic lung infection in CF. In conclusion, this study shows that none of the vaccines used could completely prevent chronic lung inflammation 4 weeks after challenge with P. aeruginosa containing alginate beads. In all immunized rats and the IFA control group, we succeeded in changing the inflammatory response from an acute type inflammation dominated by PMN leukocytes as in CF patients to a chronic type inflammation dominated by mononuclear leukocytes.
The altered abnormalities in immunized rats and the improved bacterial clearance might be of great advantage in future management of CF patients, since the ongoing lung tissue damage has been shown to be caused by elastase secreted by PMNs, which dominate the chronic P. aeruginosa lung infection in CF patients. ACKNOWLEDGMENTS The expert technical assistance of Ellen Frederiksen and Jette Pedersen is greatly appreciated. This study was supported by grants from the King Christian IX and Queen Louise Jubilee Foundation, Danish Hospital Foundation for Medical Research of Copenhagen, The Faroe Islands and Greenland grants 54/91, 47/92 and 48/93, Director Jacob Madsen and Olga Madsen,s Foundation grants 2029/1992 and 2272/1993, Ville Heises Foundation grant 5/92, the King Christian X Foundation, and Queen Louise Research Foundation grant 8/92. Abstract Objective Central pain augmentation resulting from enhanced excitatory and/or decreased inhibitory neurotransmission is a proposed mechanism underlying the pathophysiology of f

IC50 values of 0.78 and 0.41 M and shows no significant effect on the synthesis of phospholipids and triglycerides. Moreover, the metabolism of cholesterol in lysosomal CE was inhibited in macrophages by the compounds, indicating Ispinesib Ksp inhibitor that the site is in the steps between the starting point and the inhibition of cholesterol synthesis in the endoplasmic reticulum lysosome CE. Therefore, the acyl-CoA: cholesterol acyltransferase was examined in membrane fractions prepared from mouse macrophages which then causes dose–dependent inhibition by beauveriolides I and III, with IC50 values of 6.0 and 5.5 M. Thus, we have shown that beauveriolides specifically inhibit ACAT activity of t macrophages, entered Ing blocking the synthesis of EC, which leads to a reduction of Lipidtr Droplets in macrophages.
ACAT activity t Produced in the membrane fractions of mouse liver cells and Caco 2 was also inhibited, suggesting that blocking both beauveriolides ACAT 1 and 2 Practice beyond I and III Epothilone B beauveriolides antiatherogenic activity T both low density lipoprotein receptor and apolipoprotein E knockout Mice, without side effects such as diarrhea or cytotoxicity Adrenal tissues t like many synthetic ACAT inhibitors observed. Beauveriolides I and III, the first microbial cyclodepsipeptides with an anti-atherosclerotic and in vivo as much promising lead compounds for potential anti-atherosclerotic agents. Hypercholesterol Mie then causes St Changes in lipid metabolism by heterogeneous high total plasma cholesterol and lipoprotein cholesterol Low density is derived.
It is definitely to morbidity T and mortality T from heart attack together. 3-hydroxy-3-methylglutaryl-CoA reductase, a rate-limiting enzyme in the cholesterol biosynthesis, has to be effective for the inhibition of target in the treatment of hypercholesterolaemia mie And fungal compactin derivatives and mevinolin, are inhibitors of this enzyme has been clinically used as cholesterol-lowering and anti-atherosclerotic agents. On the other hand, these achievements in search of new cholesterol-lowering agents with different mechanisms are stimulated. As a result, a variety of inhibitors of microbial origin has been reported, which include hymeglusin, S Acids or zaragozic Squalestatins and pyripyropenes ferroverdins.
In the early stages of atherosclerogenesis, macrophages penetrate into the intima, efficiently take modified LDL, cholesterol and fat Acids shop as a form of neutral lipids in cytoplasmic Lipidtr Droplets and transformed into foam cells, which. To develop atherosclerosis in the artery wall Recently we have an assay system based cell synthesis of Lipidtr droplets With mouse macrophages as a model of macrophage foam cell derived. Screening for inhibitors of this system has led to the discovery of fungi beauveriolides I and III, which are members of the family cyclodepsipeptide. These compounds k Can enter dinner reducing the size S and number of cytoplasmic Fetttr Droplets in macrophages without cytotoxicity t, however, was not the final destination of this inhibition clearly. In this paper we show that beauveriolides I and III, the first orally active in microbial

Disease mortality. But w If the success of trastuzumab is a consequence of the HER2 oncogene hypothesis, it is not enough to validate. Validation of the oncogene hypothesis implies that patients with signs mechanistic inactivation of tumor HER2 trastuzumab. This evidence is currently lacking and more work for decades, in an attempt to further evaluate the mechanism of producing trastuzumab to identify Ispinesib SB-715992 prospects Tenteils gr convince contradictory and inconclusive, and a mechanistic model, and if it inhibits fa trastuzumab, the function of the HER2 oncogene was initiated. Extensive studies over the last decade have attempted to understand the molecular mechanisms of tumor development clinical activity determine t to trastuzumab against T.
The easiest assumption is based on the predetermined mAb and anti-HER2 mAb 4D5 Neut data showing that these monoclonal Body CYC202 degradation Zieloberfl che derived HER2 or induce Neut prepared. Although this seems a simple test fa cl Ture end One contradictory analysis by entering many researchers studying the effects of trastuzumab for HER2 expression in tumor cells results also with the likes of Ren cellular His reindeer assays. W Although some studies have shown that HER2 trastuzumab downregulated in tumor cells overexpressing HER2, other studies clearly show that this is not the case. Part of the complexity decided t Of T in this area was St when it was found that trastuzumab binds and internalizes a bottle surface Surface HER2, but r??appara t with HER2 on the surface Surface of Che, but only passively accompany HER2 along the normal endocytic recycling.
The most convincing proof at this point seems to be the position that trastuzumab is not the cause of down-regulation of HER2 in tumor cells may be better term. As a result, three clinical studies have not demonstrated a reduced expression of HER2 tumors in patients treated with trastuzumab. Therefore, it seems unlikely that the antitumor activity of t Is mediated by downregulation of T of trastuzumab in HER2 tumors. Page 5 Moasser Oncogene. Author manuscript 6th, April 2011 PMC. The h Important most frequent hypothesis that streamline development of trastuzumab and other anti-HER2 monoclonal rpern For most of the nineties, it inhibits the activation of HER2 by unknown ligands.
However, the adoption HER2 ligand has never been discovered, and screens, biochemical studies of the contribution of the genome of the calculation and the revelations of the crystal structure clearly shows that HER2 has no physiological ligand and ligand-sensitive functions activated by heterodimerization with its ligand to its partners, taught family. Tats Chlich the return has HER2 extracellular Ren Cathedral a constitutively active conformation, the state of the ligand bound to other proteins Family, the M Exclude possibility of activating M r T as ligands S. Thus, the assumption that the ligand binding of trastuzumab and direct activation of HER2 inhibits all but rejected at that time. Another hypothesis that has been put forward that trastuzumab interaction of HER2 with m or family SES inhibits possible to change that other interacting proteins. convincing evidence for this hypothesis has not made an appearance. In tests after trastuzumab does not inhibit HER2 HER3 interaction, fluorescence and r

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ith irinotecan and temozolomide in neuroblastoma. J Clin Oncol. 2010, 28 abstr 10593. 41. Huck JJ, Zhang M, Hyper ML, Manfredi MG. Anti tumor activity of the aurora A inhibitor MLN8237 in diffuse large B cell lymphoma preclinical model. Blood . 2008, 112 abstr 1592. 42. Zhang M, Huck J, AT9283 Sells T, et al. In vivo characterization of the aurora A kinase inhibitor MLN8237 in subcutaneous and disseminated models of human cancer. Proc Am Assoc Cancer Res. 2008, 49 abstr 5646. 43. Nawrocki ST, Medina E, Smith S, et al. The aurora kinase inhibitor MLN8237 has potent anticancer activity in CML and Ph+ ALL models and significantly increases the efficacy of nilotinib. Blood . 2008, 112 abstr 3198. 44. Gorgun G, Calabrese E, Hideshima T, et al. A novel aurora A kinase inhibitor MLN 8237 induces cytotoxicity and cell cycle arrest in multiple myeloma.
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A phase I study of XL228, a multitargeted protein kinase inhibitor, in patients with solid tumors or multiple myeloma. J Clin Oncol. 2010, 28 abstr 3105. 55. Shiotsu Y, Kiyoi H, Ozeki K, et al. KW 2449, a novel multi kinase inhibitor against FLT33, Abl, FGFR1 and aurora, suppresses the growth of AML both in vitro and in vivo. Blood . 2007, 110 abstr 1832. 56. Cortes J, Roboz GJ, Kantarjian HM, et al. A phase I dose escalation study of KW 2449, an oral multi kinase inhibitor against FLT3, Abl, FGFR1 and aurora in patients with relapsed/refractory AML, ALL and MDS or resistant/intolerant CML. Blood . 2008, 112 abstr 2967. 57. Gurtler U, Tontsch Grunt U, Jarvis M, et al. Effect of BI 811283, a novel inhibitor of aurora B kinase, on tumor senescence and apoptosis. J Clin Oncol. 2010, 28 abstr e13