Cross-sections and angular distributions for hadronic and lepton pair final states in e+e− collisions at a centre-of-mass energy near 189 GeV, measured with the OPAL detector at LEP, are presented and compared with the predictions of the Standard Model. The results are used to measure the energy dependence of the electromagnetic coupling constant αem, and to place limits on new physics as described by four-fermion contact interactions or by the exchange of a new heavy particle such as a sneutrino in supersymmetric theories with R-parity violation. A search for the indirect effects of the gravitational interaction in extra dimensions on the μ+μ− and τ+τ− final states is also presented. Submitted to European Journal of Physics C The OPAL Collaboration G.Abbiendi, K.Ackerstaff, G.Alexander, J. Allison, K.J.Anderson, S.Anderson, S.Arcelli, S.Asai, S.F.Ashby, D.Axen, G.Azuelos, A.H.Ball, E. Barberio, R.J. Barlow, J.R.Batley, S. Baumann, J. Bechtluft, T.Behnke, K.W.Bell, G.Bella, A.Bellerive, S. Bentvelsen, S. Bethke, S. Betts, O.Biebel, A.Biguzzi, I.J. Bloodworth, P. Bock, J. Böhme, O.Boeriu, D.Bonacorsi, M.Boutemeur, S. Braibant, P. Bright-Thomas, L. Brigliadori, R.M.Brown, H.J. Burckhart, P.Capiluppi, R.K.Carnegie, A.A.Carter, J.R.Carter, C.Y.Chang, D.G.Charlton, D.Chrisman, C.Ciocca, P.E.L.Clarke, E.Clay, I. Cohen, J.E.Conboy, O.C.Cooke, J. Couchman, C.Couyoumtzelis, R.L.Coxe, M.Cuffiani, S.Dado, G.M.Dallavalle, S.Dallison, R.Davis, S.De Jong, A. de Roeck, P.Dervan, K.Desch, B.Dienes, M.S.Dixit, M.Donkers, J.Dubbert, E.Duchovni, G.Duckeck, I.P.Duerdoth, P.G.Estabrooks, E. Etzion, F. Fabbri, A. Fanfani, M. Fanti, A.A. Faust, L. Feld, P. Ferrari, F. Fiedler, M. Fierro, I. Fleck, A. Frey, A. Fürtjes, D.I. Futyan, P.Gagnon, J.W.Gary, G.Gaycken, C.Geich-Gimbel, G.Giacomelli, P.Giacomelli, W.R.Gibson, D.M.Gingrich, D.Glenzinski, J.Goldberg, W.Gorn, C.Grandi, K.Graham, E.Gross, J.Grunhaus, M.Gruwé, C.Hajdu G.G.Hanson, M.Hansroul, M.Hapke, K.Harder, A.Harel, C.K.Hargrove, M.Harin-Dirac, M.Hauschild, C.M.Hawkes, R.Hawkings, R.J.Hemingway, G.Herten, R.D.Heuer, M.D.Hildreth, J.C.Hill, P.R.Hobson, A.Hocker, K.Hoffman, R.J.Homer, A.K.Honma, D.Horváth, K.R.Hossain, R.Howard, P.Hüntemeyer, P. Igo-Kemenes, D.C. Imrie, K. Ishii, F.R. Jacob, A. Jawahery, H. Jeremie, M. Jimack, C.R. Jones, P. Jovanovic, T.R. Junk, N.Kanaya, J.Kanzaki, D.Karlen, V.Kartvelishvili, K.Kawagoe, T.Kawamoto, P.I.Kayal, R.K.Keeler, R.G.Kellogg, B.W.Kennedy, D.H.Kim, A.Klier, T.Kobayashi, M.Kobel, T.P.Kokott, M.Kolrep, S.Komamiya, R.V.Kowalewski, T.Kress, P.Krieger, J. von Krogh, T.Kuhl, P.Kyberd, G.D. Lafferty, H. Landsman, D. Lanske, J. Lauber, I. Lawson, J.G. Layter, D. Lellouch, J. Letts, L. Levinson, R. Liebisch, J. Lillich, B. List, C. Littlewood, A.W.Lloyd, S.L. Lloyd, F.K. Loebinger, G.D. Long, M.J. Losty, J. Lu, J. Ludwig, D. Liu, A.Macchiolo, A.Macpherson, W.Mader, M.Mannelli, S.Marcellini, T.E.Marchant, A.J.Martin, J.P.Martin, G.Martinez, T.Mashimo, P.Mättig, W.J.McDonald, J.McKenna, E.A.Mckigney , T.J.McMahon, R.A.McPherson, F.Meijers, P.Mendez-Lorenzo, F.S.Merritt, H.Mes, I.Meyer, A.Michelini, S.Mihara, G.Mikenberg, D.J.Miller, W.Mohr, A.Montanari, T.Mori, K.Nagai, I. Nakamura, H.A.Neal, R.Nisius, S.W.O’Neale, F.G.Oakham, F.Odorici, H.O.Ogren, A.Okpara, M.J.Oreglia, S.Orito, G. Pásztor, J.R. Pater, G.N.Patrick, J. Patt, R. Perez-Ochoa, S. Petzold, P. Pfeifenschneider , J.E. Pilcher, J. Pinfold, D.E. Plane, P. Poffenberger, B. Poli, J. Polok, M.Przybycień, A.Quadt, C.Rembser, H.Rick, S. Robertson, S.A.Robins, N.Rodning, J.M.Roney, S. Rosati, K.Roscoe, A.M.Rossi, Y.Rozen, K.Runge, O.Runolfsson, D.R.Rust, K. Sachs, T. Saeki, O. Sahr, W.M. Sang, E.K.G. Sarkisyan, C. Sbarra, A.D. Schaile, O. Schaile, P. Scharff-Hansen, J. Schieck, S. Schmitt, A. Schöning, M. Schröder, M. Schumacher, C. Schwick, W.G. Scott, R. Seuster, T.G. Shears, B.C. Shen, C.H. Shepherd-Themistocleous , P. Sherwood, G.P. Siroli, A. Skuja, A.M. Smith, G.A. Snow, R. Sobie, S. Söldner-Rembold , S. Spagnolo, M. Sproston, A. Stahl, K. Stephens, K. Stoll, D. Strom, R. Ströhmer, B. Surrow, S.D.Talbot, P.Taras,

The production cross-sections for W +/- and Z bosons are measured using ATLAS data corresponding to an integrated luminosity of 4.0 pb-1 collected at a centre-ofmass energy v s = 2.76 TeV. The deca ...

Analogues structurally related to anaplastic lymphoma kinase (ALK) inhibitor 1 were optimized for metabolic stability. The results from this endeavor not only led to improved metabolic stability, pharmacokinetic parameters, and in vitro activity against clinically derived resistance mutations but also led to the incorporation of activity for focal adhesion kinase (FAK). FAK activation, via amplification and/or overexpression, is characteristic of multiple invasive solid tumors and metastasis. The discovery of the clinical stage, dual FAK/ALK inhibitor 27b, including details surrounding SAR, in vitro/in vivo pharmacology, and pharmacokinetics, is reported herein.

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Abstract Anaplastic lymphoma kinase (ALK) is constitutively activated in a number of human cancer types due to chromosomal translocations, point mutations, and gene amplification and has emerged as an excellent molecular target for cancer therapy. Here we report the identification and preclinical characterization of CEP-28122, a highly potent and selective orally active ALK inhibitor. CEP-28122 is a potent inhibitor of recombinant ALK activity and cellular ALK tyrosine phosphorylation. It induced concentration-dependent growth inhibition/cytotoxicity of ALK-positive anaplastic large-cell lymphoma (ALCL), non-small cell lung cancer (NSCLC), and neuroblastoma cells, and displayed dose-dependent inhibition of ALK tyrosine phosphorylation in tumor xenografts in mice, with substantial target inhibition (>90%) for more than 12 hours following single oral dosing at 30 mg/kg. Dose-dependent antitumor activity was observed in ALK-positive ALCL, NSCLC, and neuroblastoma tumor xenografts in mice administered CEP-28122 orally, with complete/near complete tumor regressions observed following treatment at doses of 30 mg/kg twice daily or higher. Treatment of mice bearing Sup-M2 tumor xenografts for 4 weeks and primary human ALCL tumor grafts for 2 weeks at 55 or 100 mg/kg twice daily led to sustained tumor regression in all mice, with no tumor reemergence for more than 60 days postcessation of treatment. Conversely, CEP-28122 displayed marginal antitumor activity against ALK-negative human tumor xenografts under the same dosing regimens. Administration of CEP-28122 was well tolerated in mice and rats. In summary, CEP-28122 is a highly potent and selective orally active ALK inhibitor with a favorable pharmaceutical and pharmacokinetic profile and robust and selective pharmacologic efficacy against ALK-positive human cancer cells and tumor xenograft models in mice. Mol Cancer Ther; 11(3); 670–9. ©2011 AACR.

The elaboration of a novel scaffold for the inhibition of JAK2 and FAK kinases was targeted in order to provide a dual inhibitor that could target divergent pathways for tumor cell progression.

Members of the JAK family of nonreceptor tyrosine kinases play a critical role in the growth and progression of many cancers and in inflammatory diseases. JAK2 has emerged as a leading therapeutic target for oncology, providing a rationale for the development of a selective JAK2 inhibitor. A program to optimize selective JAK2 inhibitors to combat cancer while reducing the risk of immune suppression associated with JAK3 inhibition was undertaken. The structure-activity relationships and biological evaluation of a novel series of compounds based on a 1,2,4-triazolo[1,5-a]pyridine scaffold are reported. Para substitution on the aryl at the C8 position of the core was optimum for JAK2 potency (17). Substitution at the C2 nitrogen position was required for cell potency (21). Interestingly, meta substitution of C2-NH-aryl moiety provided exceptional selectivity for JAK2 over JAK3 (23). These efforts led to the discovery of CEP-33779 (29), a novel, selective, and orally bioavailable inhibitor of JAK2.

Anaplastic lymphoma kinase (ALK) is a promising therapeutic target for the treatment of cancer, supported by considerable favorable preclinical and clinical activities over the past several years and culminating in the recent FDA approval of the ALK inhibitor crizotinib. Through a series of targeted modifications on an ALK inhibitor diaminopyrimidine scaffold, our research group has driven improvements in ALK potency, kinase selectivity, and overall pharmaceutical properties. Optimization of this scaffold has led to the identification of a potent and efficacious inhibitor of ALK, 25b. A striking feature of 25b over previously described ALK inhibitors is its >600-fold selectivity over insulin receptor (IR), a closely related kinase family member. Most importantly, 25b exhibited dose proportional escalation in rat compared to compound 3 which suffered dose limiting absorption preventing further advancement. Compound 25b exhibited significant in vivo antitumor efficacy when dosed orally in an ALK-positive ALCL tumor xenograft model in SCID mice, warranting further assessment in advanced preclinical models.

Anaplastic lymphoma kinase (ALK) was originally identified as the oncogenic NPM (nucleophosmin)-ALK fusion protein due to a t (2;5) chromosomal translocation in anaplastic large cell lymphomas (ALCL). Many other chromosomal rearrangements or gene mutations/amplification leading to enhanced ALK activity have subsequently been identified and characterized in a number of human cancer types. The recent reports of EML4 (echinoderm microtubule-associated protein-like 4)-ALK oncogenic proteins in non-small cell lung cancer (NSCLC) and the identification of ALK activating point mutations and gene amplification in neuroblastoma have indicated ALK as a potential major therapeutic target for human cancers. Here we report the identification and preclinical characterization of CEP-28122, a highly potent and selective orally active ALK inhibitor. CEP-28122 is a potent inhibitor of recombinant ALK activity (IC50 of 3 nM) and NPM-ALK tyrosine phosphorylation in ALCL cells (IC50 of 20-30 nM). It is selective over a broad panel of protein kinases and a panel of receptors and ion channels with greater than 300-fold selectivity for insulin receptor. CEP-28122 induced concentration-dependent growth inhibition and cytotoxicity of ALK-positive ALCL and NSCLC cells with minimal activity against ALK-negative lymphoma and leukemia cells as well as ALK-negative NSCLC cells at concentrations up to 3 μM. CEP-28122 exhibited favorable oral bioavailability (F = 37-71% across species) with adequate tissue distribution in rodents. It displayed dose-dependent inhibition of NPM-ALK tyrosine phosphorylation in human ALCL tumor xenografts in mice with complete target inhibition (> 90%) for more than 12 h following single oral dosing at 30 mg/kg. Dose-dependent anti-tumor activity was observed in NPM-ALK-positive Sup-M2 and Karpas-299 ALCL tumor xenografts and EML4-ALK-positive NCI-H2228 and NCI-H3122 tumor xenografts in mice dosed with CEP-28122, bid, po, with complete or near complete tumor regressions observed following 2 weeks of treatment with CEP-28122 at 30 mg/kg or higher. Treatment of mice bearing Sup-M2 tumor xenografts or primary human ALCL tumorgrafts with CEP-28122 at 55 or 100 mg/kg bid, po, for 4 weeks led to sustained tumor regression in all mice, with no tumor re-emergence in any mouse up to 60 days post cessation of CEP-28122 treatment. On the contrary, CEP-28122 displayed marginal anti-tumor activity against ALK-negative lymphoma and NSCLC tumor xenografts under the same dosing regimens. It was well tolerated with all dosing regimens in mice and rats with no overt toxicity and no compound-related body weight loss. CEP-28122 advanced into preclinical development based on its potency, selectivity and overall favorable pharmacological, pharmaceutical and safety profiles. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3574. doi:10.1158/1538-7445.AM2011-3574

Evolution of the process strategies to prepare CEP-28122, an anaplastic lymphoma kinase (ALK) inhibitor, is presented. The initial medicinal chemistry route, used for the preparation of key supplies for biological screening, is reviewed. In addition, the process research and development of the final optimized process for manufacture of preclinical and clinical supplies is discussed. Details regarding a blocking group strategy for selective nitration; discovery of a one-pot transfer hydrogenation to effect a reductive amination, nitro group reduction, and dehalogenation; an enzymatic resolution of a critical intermediate; and the discovery of a novel, stable, in situ generated mixed mesylate hydrochloride salt of the API are disclosed.

A novel 2,7-disubstituted-pyrrolo[2,1-f][1,2,4]triazine scaffold has been designed as a new kinase inhibitor platform mimicking the bioactive conformation of the well-known diaminopyrimidine motif. The design, synthesis, and validation of this new pyrrolo[2,1-f][1,2,4]triazine scaffold will be described for inhibitors of anaplastic lymphoma kinase (ALK). Importantly, incorporation of appropriate potency and selectivity determinants has led to the discovery of several advanced leads that were orally efficacious in animal models of anaplastic large cell lymphoma (ALCL). A lead inhibitor (30) displaying superior efficacy was identified and in depth in vitro/in vivo characterization will be presented.

There are numerous published studies establishing a link between reactive metabolite formation and toxicity of various drugs. Although the correlation between idiosyncratic reactions and reactive metabolite formation is not 1:1, the association between the two is such that many pharmaceutical companies now monitor for reactive metabolites as a standard part of drug candidate testing and selection. The most common method involves in vitro human microsomal incubations in the presence of a thiol trapping agent, such as glutathione (GSH), followed by LC/MS analysis. In this study, we describe several 2,7-disubstituted-pyrrolotriazine analogues that are extremely potent reactive metabolite precursors. Utilizing a UPLC/UV/MS method, unprecedented levels of GSH adducts were measured that are 5-10 times higher than previously reported for high reactive metabolite-forming compounds such as clozapine and troglitazone.

Accumulating evidence suggests that autoreactive plasma cells play an important role in systemic lupus erythematosus (SLE). In addition, several proinflammatory cytokines promote autoreactive B cell maturation and autoantibody production. Hence, therapeutic targeting of such cytokine pathways using a selective JAK2 inhibitor, CEP-33779 (JAK2 enzyme IC(50) = 1.3 nM; JAK3 enzyme IC(50)/JAK2 enzyme IC(50) = 65-fold), was tested in two mouse models of SLE. Age-matched, MRL/lpr or BWF1 mice with established SLE or lupus nephritis, respectively, were treated orally with CEP-33779 at 30 mg/kg (MRL/lpr), 55 mg/kg or 100 mg/kg (MRL/lpr and BWF1). Studies included reference standard, dexamethasone (1.5 mg/kg; MRL/lpr), and cyclophosphamide (50 mg/kg; MRL/lpr and BWF1). Treatment with CEP-33779 extended survival and reduced splenomegaly/lymphomegaly. Several serum cytokines were significantly decreased upon treatment including IL-12, IL-17A, IFN-α, IL-1β, and TNF-α. Anti-nuclear Abs and frequencies of autoantigen-specific, Ab-secreting cells declined upon CEP-33779 treatment. Increased serum complement levels were associated with reduced renal JAK2 activity, histopathology, and spleen CD138(+) plasma cells. The selective JAK2 inhibitor CEP-33779 was able to mitigate several immune parameters associated with SLE advancement, including the protection and treatment of mice with lupus nephritis. These data support the possibility of using potent, orally active, small-molecule inhibitors of JAK2 to treat the debilitative disease SLE.

The JAK2/STAT pathway has important roles in hematopoiesis. With the discovery of the JAK2 V617F mutation and its presence in many patients with myeloproliferative neoplasms, research in the JAK2 inhibitor arena has dramatically increased. We report a novel series of potent JAK2 inhibitors containing a 2,7-pyrrolotriazine core. To minimize potential drug-induced toxicity, targets were analyzed for the ability to form a glutathione adduct. Glutathione adduct formation was decreased by modification of the aniline substituent at C2.

64 Background: While various multi-gene predictors (MGPs) of chemotherapy response have been developed based on cancer patient primary tissues or cancer cell-lines, the accuracy and consistency of these predictors remain a concern in clinical validation studies. In this study we developed four unique MGPs for chemotherapy response from breast cancer cell lines and performed a systematic evaluation of the performance of these MGPs using data from five distinct clinical trials.METHODSForty-six immortalized breast cancer cell-lines were exposed to various concentrations of drug combinations [paclitaxel, 5-fluorouracil, doxorubicin, cyclophosphamide (TFAC); 5-fluorouracil, doxorubicin, cyclophosphamide (FAC); 5-fluorouracil, epirubicin, cyclophosphamide (FEC) and epirubicin, cyclophosphamide (EC)] using an in vitro chemosensitivity assay. Utilizing publicly available breast cancer cell-line microarray data, genes highly associated with in vitro chemosensitivity were selected as candidate MGPs. Five independent and publicly available clinical trials were used for validation. In three of these clinical trials patients were treated by TFAC, while EC, FAC or FEC were used in the other two trials. All five studies involved neoadjuvant chemotherapy treatment, and pathologic complete response (pCR) was used as the endpoint. The association of MGPs with pCR was assessed using receiver-operator curve (ROC) analysis and area under the ROC (AUC) was used to evaluate the performance of prediction.RESULTSIn five independent clinical trials, the MGPs predicted patient pCR to EC, FAC/FEC and three TFAC treatments with an AUC of, 0.671, 0.632, 0.735, 0.738 and 0.647 respectively.CONCLUSIONSIn the five independent clinical trials in which patients were treated by various chemotherapy agents, the performance of MGPs is promising. These results demonstrate the feasibility of using breast cancer cell-line derived MGPs to predict breast cancer patients' chemotherapy responses.