المؤلفون: Claudia A. Chiriboga, Claudio Bruno, Tina Duong, Dirk Fischer, Eugenio Mercuri, Janbernd Kirschner, Anna Kostera-Pruszczyk, Birgit Jaber, Ksenija Gorni, Heidemarie Kletzl, Imogen Carruthers, Carmen Martin, Francis Warren, Renata S. Scalco, Kathryn R. Wagner, Francesco Muntoni, Nicolas Deconinck, Irina Balikova, Inge Joniau, Valentine Tahon, Sylvia Wittevrongel, Nathalie Goemans, Catherine Cassiman, Lies Prove, Lisa Vancampenhout, Marleen van den Hauwe, Annelies Van Impe, Claude Cances, Vincent Soler, Lauriane Maillard De La Morandais, Delphine Vovan, Pascal Cintas, Françoise Auriol, Marianne Mus, Gwennaelle Alphonsa, Valerie Bellio, Olaia Gil Mato, Florence Flamein, Cécile Evrard, Amina Ziouche, Ikram Bouacha-Allou, Philippe Debruyne, Gilles Derlyn, Sabine Defoort, Florian Leroy, Loïc Danjoux, Isabelle Desguerre, Dominique Bremond-Gignac, Maxence Rateuax, Elodie Deladrière, Carole Vuillerot, Quentin Veillerot, Bénédicte Sibille-Dabadi, Aurélie Barrière, Marie Tinat, Manel Saidi, Stephanie Fontaine, Camille De Montferrand, Laure Le-Goff, Aurélie Portefaix, Ulrike Walther Louvier, Pierre-André Duval, Pascale Caradec, Souad Touati, Alberto Zamora Herranz, Jan Bollig, ù Fanni Molnár, Sibylle Vogt, Astrid Pechmann, David Schorling, Sabine Wider, Heike Kölbel, Ulrike Schara, Frederik Braun, Andrea Gangfuss, Tim Hagenacker, Anja Eckstein, Dirk Dekowski, Michael Oeverhaus, Mareile Stoehr, Barbara Andres, Karin Smuda, Enrico Bertini, Adele D'Amico, Sergio Petroni, Paola Valente, Anna Maria Bonetti, Adelina Carlesi, Irene Mizzoni, Marina Pedemonte, Noemi Brolatti, Enrico Priolo, Giuseppe Rao, Lorenza Sposetti, Simone Morando, Giacomo Comi, Silvia Osnaghi, Valeria Minorini, Francesca Abbati, Federica Fassini, Michaela Foà, Maria Amalia Lopopolo, Francesca Magri, Alessandra Govoni, Megi Meneri, Valeria Parente, Laura Antonaci, Maria Carmela Pera, Marika Pane, Giulia Maria Amorelli, Costanza Barresi, Guglielmo D'Amico, Lorenzo Orazi, Giorgia Coratti, Roberto De Sanctis, Giuseppe Vita, Maria Sframeli, Gian Luca Vita, Pasquale Aragona, Leandro Inferrera, Elisa Imelde Postorino, Daniela Montanini, Vincenzo Di Bella, Concetta Donato, Elisabetta Calà, Ludo Van der Pol, Jos Aalbers, Joke de Boer, Saskia Imhof, Pascale Cooijmans, Thijs Ruyten, Danny Van Der Woude, Beata Klimaszewska, Dominika Romańczak, Zuzanna Gierlak-Wójcicka, Malwina Kępa, Adam Sikorski, Marcin Sobieraj, Anna Lusakowska, Biruta Kierdaszuk, Karolina Czeczko, Bettina Henzi, Konstantin Gugleta, Akos Kusnyerik, Patricia Siems, Sabina Akos, Nora Frei, Christine Seppi, Christine Wondrusch Haschke, Michela Guglieri, Volker Straub, Richard Bell, Mahmoud Nassar, Stuart Page, Michael Patrick Clarke, Aedheen Regan, Anna Mayhew, Robert Muni Lofra, Deepak Parasuraman, Simone Bruschi, Abdul-Jabbar Ghauri, Andrew Castle, Saima Naqvi, Nicola Patt, Mariacristina Scoto, Federica Trucco, Robert H Henderson, Roopen Kukadia, Will Moore, Evelin Milev, Catherine Rye, Victoria Selby, Amy Wolfe, Basil Darras, Anna Maria Baglieri, Anne Fulton, Courtney Lucken, Elizabeth Maczek, Amy Pasternak, Claudia A Chiriboga, Steven Kane, Ma Edylin M Bautista, Eileen Frommer, Noelle Pensec, Rachel Salazar, Cara Yochai, Rafael Rodrigues-Torres, Manroop Chawla, John Day, Shannon Beres, Richard Gee, Sally Dunaway Young, Richard Finkel, Aledie Navas Nazario, Airaj Fasiuddin, Julie A Wells, Jennifer Wilson, Debbie Berry, Virgina Rizzo, Julie Duke, Migvis Monduy, Jorge Collado.

المساهمون: Chiriboga, Claudia A., Bruno, Claudio, Duong, Tina, Fischer, Dirk, Mercuri, Eugenio, Kirschner, Janbernd, Kostera-Pruszczyk, Anna, Jaber, Birgit, Gorni, Ksenija, Kletzl, Heidemarie, Carruthers, Imogen, Martin, Carmen, Warren, Franci, Scalco, Renata S., Wagner, Kathryn R., Muntoni, Francesco, Deconinck, Nicola, Balikova, Irina, Joniau, Inge, Tahon, Valentine, Wittevrongel, Sylvia, Goemans, Nathalie, Cassiman, Catherine, Prove, Lie, Vancampenhout, Lisa, van den Hauwe, Marleen, Van Impe, Annelie, Cances, Claude, Soler, Vincent, Maillard De La Morandais, Lauriane, Vovan, Delphine, Cintas, Pascal, Auriol, Françoise, Mus, Marianne, Alphonsa, Gwennaelle, Bellio, Valerie, Gil Mato, Olaia, Flamein, Florence, Evrard, Cécile, Ziouche, Amina, Bouacha-Allou, Ikram, Debruyne, Philippe, Derlyn, Gille, Defoort, Sabine, Leroy, Florian, Danjoux, Loïc, Desguerre, Isabelle, Bremond-Gignac, Dominique, Rateuax, Maxence, Deladrière, Elodie, Vuillerot, Carole, Veillerot, Quentin, Sibille-Dabadi, Bénédicte, Barrière, Aurélie, Tinat, Marie, Saidi, Manel, Fontaine, Stephanie, De Montferrand, Camille, Le-Goff, Laure, Portefaix, Aurélie, Walther Louvier, Ulrike, Duval, Pierre-André, Caradec, Pascale, Touati, Souad, Zamora Herranz, Alberto, Bollig, Jan, Fanni Molnár, Ù, Vogt, Sibylle, Pechmann, Astrid, Schorling, David, Wider, Sabine, Kölbel, Heike, Schara, Ulrike, Braun, Frederik, Gangfuss, Andrea, Hagenacker, Tim, Eckstein, Anja, Dekowski, Dirk, Oeverhaus, Michael, Stoehr, Mareile, Andres, Barbara, Smuda, Karin, Bertini, Enrico, D'Amico, Adele, Petroni, Sergio, Valente, Paola, Maria Bonetti, Anna, Carlesi, Adelina, Mizzoni, Irene, Pedemonte, Marina, Brolatti, Noemi, Priolo, Enrico, Rao, Giuseppe, Sposetti, Lorenza, Morando, Simone, Comi, Giacomo, Osnaghi, Silvia, Minorini, Valeria

مصطلحات موضوعية: Evrysdi, Pharmacodynamic, Risdiplam, Safety, Spinal muscular atrophy

الوصف: Introduction: Risdiplam is a survival of motor neuron 2 (SMN2) splicing modifier for the treatment of patients with spinal muscular atrophy (SMA). The JEWELFISH study (NCT03032172) was designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of risdiplam in previously treated pediatric and adult patients with types1–3 SMA. Here, an analysis was performed after all patients had received at least 1year of treatment with risdiplam. Methods: Patients with a confirmed diagnosis of 5q-autosomal recessive SMA between the ages of 6months and 60years were eligible for enrollment. Patients were previously enrolled in the MOONFISH study (NCT02240355) with splicing modifier RG7800 or treated with olesoxime, nusinersen, or onasemnogene abeparvovec. The primary objectives of the JEWELFISH study were to evaluate the safety and tolerability of risdiplam and investigate the PK after 2years of treatment. Results: A total of 174 patients enrolled: MOONFISH study (n = 13), olesoxime (n = 71 patients), nusinersen (n = 76), onasemnogene abeparvovec (n = 14). Most patients (78%) had three SMN2 copies. The median age and weight of patients at enrollment was 14.0years (1–60years) and 39.1kg (9.2–108.9kg), respectively. About 63% of patients aged 2–60years had a baseline total score of less than 10 on the Hammersmith Functional Motor Scale–Expanded and 83% had scoliosis. The most common adverse event (AE) was upper respiratory tract infection and pyrexia (30 patients each; 17%). Pneumonia (four patients; 2%) was the most frequently reported serious AE (SAE). The rates of AEs and SAEs per 100 patient-years were lower in the second 6-month period compared with the first. An increase in SMN protein was observed in blood after risdiplam treatment and was comparable across all ages and body weight quartiles. Conclusions: The safety and PD of risdiplam in patients who were previously treated were consistent with those of treatment-naïve patients.

وصف الملف: ELETTRONICO

العلاقة: info:eu-repo/semantics/altIdentifier/wos/WOS:000929942600001; volume:12; firstpage:543; lastpage:557; numberofpages:15; journal:NEUROLOGY AND THERAPY; https://hdl.handle.net/11567/1156274Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85148078301

الإتاحة: https://doi.org/10.1007/s40120-023-00444-1Test
https://hdl.handle.net/11567/1156274Test

المؤلفون: Karen Collins, Donald Wojciechowicz, Judy Lucas, Nancy Torres, Jeremy I. Levin, Yongbo Hu, Cilien Hanna, Dan M. Berger, Edward J. Salaski, Eileen Frommer, Minu Dutia, Wang Xiaolun, Dennis Powell

المصدر: Journal of Medicinal Chemistry. 53:7874-7878

مصطلحات موضوعية: Models, Molecular, Proto-Oncogene Proteins B-raf, Indazoles, Transplantation, Heterologous, Mutant, Antineoplastic Agents, Pharmacology, Mice, Structure-Activity Relationship, Pyrimidine analogue, chemistry.chemical_compound, Pharmacokinetics, In vivo, Cell Line, Tumor, Drug Discovery, Animals, Humans, Chemistry, Kinase, Bridged Bicyclo Compounds, Heterocyclic, humanities, Pyrimidines, Biochemistry, Mutation, Pyrazoles, Molecular Medicine, Drug Screening Assays, Antitumor, Selectivity, Lead compound, Neoplasm Transplantation

الوصف: Novel indazolylpyrazolo[1,5-a]pyrimidine analogues have been prepared and found to be extremely potent type I B-Raf inhibitors. The lead compound shows good selectivity against a panel of 60 kinases, possesses a desirable pharmacokinetic profile, and demonstrates excellent in vivo antitumor efficacy in B-Raf mutant xenograft models.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f5cfb7f80cde520202634116ccfc59adTest
https://doi.org/10.1021/jm1007566Test

المؤلفون: Yongbo Hu, Karen Collins, Edward J. Salaski, Nancy Torres, Eileen Frommer, Dennis Powell, Wang Xiaolun, Jeremy I. Levin, Donald Wojciechowicz, Dan Maarten Berger

المصدر: Bioorganic & Medicinal Chemistry Letters. 19:6571-6574

مصطلحات موضوعية: Models, Molecular, Proto-Oncogene Proteins B-raf, Molecular model, Stereochemistry, Clinical Biochemistry, Pharmaceutical Science, Biochemistry, Chemical synthesis, Substrate Specificity, Structure-Activity Relationship, Pyrimidine analogue, Drug Discovery, Protein Kinase Inhibitors, Molecular Biology, chemistry.chemical_classification, Molecular Structure, biology, Kinase, Organic Chemistry, In vitro, Pyrimidines, Enzyme, chemistry, Enzyme inhibitor, biology.protein, Pyrazoles, Molecular Medicine, Signal transduction

الوصف: A series of pyrazolo[1,5-alpha]pyrimidine analogs has been prepared and found to be potent and selective B-Raf inhibitors. Molecular modeling suggests they bind to the active conformation of the enzyme.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::981acddc510eaf8186f924c43131f046Test
https://doi.org/10.1016/j.bmcl.2009.10.030Test

المؤلفون: Nancy Torres, Eileen Frommer, Bloom Jonathan David, Karen Collins, Dunnick Alejandro Lee, George Diamantidis, Yongbo Hu, Minu Dutia, Christoph W. Zapf, Zhang Chunchun, Darrin William Hopper, Dan Maarten Berger, Donald Wojciechowicz, Dennis Powell, Martin Di Grandi, Jeremy I. Levin

المصدر: Bioorganic & Medicinal Chemistry Letters. 19:6957-6961

مصطلحات موضوعية: Proto-Oncogene Proteins B-raf, Pyridines, Isostere, Stereochemistry, Clinical Biochemistry, Pharmaceutical Science, Antineoplastic Agents, Biochemistry, Chemical synthesis, chemistry.chemical_compound, Cell Line, Tumor, Drug Discovery, Humans, Enzyme Inhibitors, Cytotoxicity, Molecular Biology, Cell Proliferation, chemistry.chemical_classification, Indazole, biology, Bicyclic molecule, Cell growth, Organic Chemistry, Pyrimidines, Enzyme, chemistry, Enzyme inhibitor, biology.protein, Pyrazoles, Molecular Medicine

الوصف: A novel series of pyrazolo[1,5-a]pyrimidines bearing a 3-hydroxyphenyl group at C(3) and substituted tropanes at C(7) have been identified as potent B-Raf inhibitors. Exploration of alternative functional groups as a replacement for the C(3) phenol demonstrated indazole to be an effective isostere. Several compounds possessing substituted indazole residues, such as 4e, 4p, and 4r, potently inhibited cell proliferation at submicromolar concentrations in the A375 and WM266 cell lines, and the latter two compounds also exhibited good therapeutic indices in cells.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6346230a46b93ee107f73ab7d8869701Test
https://doi.org/10.1016/j.bmcl.2009.10.058Test

المؤلفون: Rob Van Soest, Akbar Tahir, Robert Mallon, Irwin Hollander, David E. Williams, Raymond J. Andersen, Larry Feldberg, Eileen Frommer

المصدر: Journal of Natural Products. 72:1106-1109

مصطلحات موضوعية: Sesterterpenes, Stereochemistry, medicine.medical_treatment, Pharmaceutical Science, Marine Biology, Tumor cells, Biology, Animal origin, Analytical Chemistry, Carteriospongia foliascens, Endopeptidases, Drug Discovery, medicine, Animals, Humans, Protease Inhibitors, Pharmacology, Protease, Molecular Structure, Extramural, Organic Chemistry, biology.organism_classification, Porifera, Sponge, Complementary and alternative medicine, Biochemistry, Indonesia, Molecular Medicine

الوصف: Two new 20,24-bishomo-25-norscalaranes, compounds 1 and 2, and two new and two known 20,24-bishomoscalaranes, compounds 3-6, have been isolated from the Indonesian marine sponge Carteriospongia foliascens. The structures of 1-6 were determined by spectroscopic analysis. Compounds 1 and 3-6 inhibit RCE-protease activity.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bd31a3b2af8ada25421ea61a271139b4Test
https://doi.org/10.1021/np900042rTest

المؤلفون: Eileen Frommer, Irwin Hollander, Robert Mallon

المصدر: Analytical Biochemistry. 286:129-137

مصطلحات موضوعية: Insecta, Time Factors, medicine.medical_treatment, Molecular Sequence Data, Lysine, Protein Prenylation, Biophysics, Peptide, Tripeptide, Cleavage (embryo), Biochemistry, Cell Line, Proto-Oncogene Proteins p21(ras), Microtiter plate, Endopeptidases, medicine, Animals, Humans, Amino Acid Sequence, Amino Acids, Cloning, Molecular, Molecular Biology, Chromatography, High Pressure Liquid, chemistry.chemical_classification, Protease, Dose-Response Relationship, Drug, Cell Biology, Recombinant Proteins, Amino acid, Spectrometry, Fluorescence, Enzyme, chemistry, Peptides

الوصف: A human gene responsible for one of the steps in Ras post-translational modification and membrane localization, hRCE1, encodes a 35-kDa membrane-associated endoprotease. We examined hRCE1 activity using farnesylated 9 aa peptides with the core sequence, KSKTKC(farnesyl)VIM [(farnesyl) = (f)], from the C-terminus of K-Ras. We first demonstrated hRCE1 specificity in cleavage location and endoproteolysis. We then describe a direct fluorescent microtiter plate assay. We demonstrated that hRCE1 protease cleaved KSKTKC(f)VIM peptides between the C(f) and V positions, generating KSKTKC(f) and the corresponding tripeptides as products. We found that the sequence KSKTKC(f)VI was a better substrate for hRCE1 than KSKTKC(f)VIM. We also found that hRCE1 cleaved modified versions of KSKTKC(f)VIM that incorporated either MCA or ABZ fluorescent chromophores at the N-terminus, and quenching-group-containing amino acids at the V or M, but not the I, amino acid positions of VIM. The quenching-group-containing amino acids used were either QS (dinitrophenyldiaminopropionic acid) or QL (lysine ϵ-dinitrophenyl). Cleavage of KSKTKC(f)VIM and modified versions of this peptide by hRCE1 was initially evaluated by HPLC product resolution and quantitation. The hRCE1 cleavage of quenched peptides enabled us to directly monitor proteolytic activity in a 96-well microtiter fluorescent plate assay. The microtiter format assay was validated by its sensitivity to RPI, an inhibitor of prenyl protein protease. A direct fluorescent assay provides an effective tool for further characterization of this enzyme and also for detection of novel inhibitors.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::61941e1f9e1712622baaeefd945f61a7Test
https://doi.org/10.1006/abio.2000.4795Test

المؤلفون: Steven C. Kim, Frederick Lee, Eileen Frommer, Mengxiao Shi, Yongbo Hu, Donald Wojciechowicz, Robert Mallon, Greg Ciszewski, Dan Maarten Berger, Karen Collins, Ariamala Gopalsamy, Larry Feldberg

المصدر: Bioorganic & Medicinal Chemistry Letters. 19:6890-6892

مصطلحات موضوعية: Proto-Oncogene Proteins B-raf, Pyrimidine, Stereochemistry, medicine.drug_class, Clinical Biochemistry, Pharmaceutical Science, Antineoplastic Agents, Carboxamide, Biochemistry, chemistry.chemical_compound, Drug Discovery, medicine, Humans, Enzyme Inhibitors, Molecular Biology, chemistry.chemical_classification, biology, Kinase, Organic Chemistry, Hit to lead, Pyrimidines, Enzyme, chemistry, Enzyme inhibitor, Drug Design, biology.protein, Pyrazoles, Molecular Medicine, Signal transduction, Lead compound

الوصف: Our continued effort towards optimization of the pyrazolo[1,5-a]pyrimidine scaffold as B-Raf kinase inhibitors is described. Structure guided design was utilized to introduce kinase hinge region interacting groups in the 2-position of the scaffold. This strategy led to the identification of lead compound 9 with enhanced enzyme and cellular potency, while maintaining good selectivity over a number of kinases.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9a6af29a6344c217dfecdc0daf235230Test
https://doi.org/10.1016/j.bmcl.2009.10.074Test

المؤلفون: Edward J. Salaski, Wang Xiaolun, Dennis Powell, Donald Wojciechowicz, Eileen Frommer, Dan M. Berger, Karen Collins, Yongbo Hu

المصدر: Bioorganicmedicinal chemistry letters. 21(23)

مصطلحات موضوعية: Models, Molecular, Niacinamide, Proto-Oncogene Proteins B-raf, Pyridines, Clinical Biochemistry, Pharmaceutical Science, Isoindoles, Biochemistry, chemistry.chemical_compound, Structure-Activity Relationship, Drug Discovery, Potency, Enzyme Inhibitors, Molecular Biology, Molecular Structure, Chemistry, Kinase, Phenylurea Compounds, Organic Chemistry, Benzenesulfonates, Imidazoles, Isoindoline, Sorafenib, Combinatorial chemistry, Enzyme Activation, Drug Design, Molecular Medicine, Structure based, Phthalazines, Selectivity

الوصف: Structure-guided design led to the discovery of novel chemical scaffolds for B-Raf inhibitors. Both type I and type II kinase inhibitors have been explored and lead compounds with good potency and excellent selectivity have been identified.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cc2b84f81a40df7101d2b4f6a8635c87Test
https://pubmed.ncbi.nlm.nih.gov/22024030Test

المؤلفون: Mengxiao Shi, Larry Feldberg, Frederick Lee, Yongbo Hu, Donald Wojciechowicz, Ariamala Gopalsamy, Steven C. Kim, Karen Collins, Robert Mallon, Eileen Frommer

المصدر: Bioorganicmedicinal chemistry letters. 20(8)

مصطلحات موضوعية: chemistry.chemical_classification, Models, Molecular, Proto-Oncogene Proteins B-raf, Scaffold, Thienopyridine, Pyrimidine, Kinase, Organic Chemistry, Clinical Biochemistry, Pharmaceutical Science, Biochemistry, Combinatorial chemistry, chemistry.chemical_compound, Structure-Activity Relationship, Enzyme, Pyrimidines, chemistry, Drug Discovery, Molecular Medicine, Pharmacophore, Molecular Biology, Lead compound, Cell potency, Protein Kinase Inhibitors

الوصف: In continuation of our efforts toward hit identification and optimization for a B-Raf kinase project, we have employed a scaffold hopping strategy. The original HTS hit scaffold pyrazolo[1,5-a]pyrimidine was replaced with different thienopyrimidine and thienopyridine scaffolds to append the optimal pharmacophore moieties in order to generate novel B-raf kinase inhibitors with desirable potency and properties. This strategy led to the identification of additional lead compound 11b which had good enzyme and cell potency, while maintaining selectivity over a number of kinases.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::217a9762ff7cb7662f0b9e91c001712cTest
https://pubmed.ncbi.nlm.nih.gov/20307980Test

المؤلفون: Frederick Lee, Ariamala Gopalsamy, Yongbo Hu, Greg Ciszewski, Donald Wojciechowicz, Karen Collins, Steven C. Kim, Larry Feldberg, Eileen Frommer, Robert Mallon

المصدر: ChemInform. 40

مصطلحات موضوعية: chemistry.chemical_compound, Pyrimidine, Chemistry, Colorectal cancer, Kinase, Cancer research, medicine, Identification (biology), Raf kinase, General Medicine, Signal transduction, medicine.disease, Small molecule

الوصف: B-Raf kinase plays a critical role in the Raf-MEK-ERK signaling pathway and inhibitors of B-Raf could be used in the treatment of melanomas, colorectal cancer, and other Ras related human cancers. We have identified novel small molecule pyrazolo[1,5-a]pyrimidine derivatives as B-Raf kinase inhibitors. Structure-activity relationship was generated for various regions of the scaffold to improve the biochemical profile.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::5d68a32fa0b4a6cf2b9d5f0e9b5fa80aTest
https://doi.org/10.1002/chin.200940153Test