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1. Design, synthesis and biological evaluation of novel aminopyrazole- and 7-azaindole-based Nek1 inhibitors and their effects on zebrafish kidney development.

Author

Pilakowski J, Baumann G, Shih YH, Meckel T, and Schmidt B

Subjects
Animals, Dose-Response Relationship, Drug, Indoles chemical synthesis, Indoles chemistry, Kidney growth & development, Kidney metabolism, Molecular Structure, NIMA-Related Kinase 1 metabolism, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Pyrazoles chemical synthesis, Pyrazoles chemistry, Structure-Activity Relationship, Zebrafish, Drug Design, Indoles pharmacology, Kidney drug effects, NIMA-Related Kinase 1 antagonists & inhibitors, Protein Kinase Inhibitors pharmacology, Pyrazoles pharmacology
Abstract

NIMA-related protein kinase Nek1 is crucially involved in cell cycle regulation, DNA repair and microtubule regulation and dysfunctions of Nek1 play key roles in amyotrophic lateral sclerosis (ALS), polycystic kidney disease (PKD) and several types of radiotherapy resistant cancer. Targeting of Nek1 could reveal a new class of radiosensitizing substances and provide useful tools to better understand the aforementioned diseases. In this report we explore substituted aminopyrazoles and 7-azaindoles as potent inhibitors for the Nek1 kinase domain and examine their effect on kidney organogenesis in Danio rerio., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Published
2021
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2. Pan-cancer analysis of pre-diagnostic blood metabolite concentrations in the European Prospective Investigation into Cancer and Nutrition

Author

Marie Breeur, Pietro Ferrari, Laure Dossus, Mazda Jenab, Mattias Johansson, Sabina Rinaldi, Ruth C. Travis, Mathilde His, Tim J. Key, Julie A. Schmidt, Kim Overvad, Anne Tjønneland, Cecilie Kyrø, Joseph A. Rothwell, Nasser Laouali, Gianluca Severi, Rudolf Kaaks, Verena Katzke, Matthias B. Schulze, Fabian Eichelmann, Domenico Palli, Sara Grioni, Salvatore Panico, Rosario Tumino, Carlotta Sacerdote, Bas Bueno-de-Mesquita, Karina Standahl Olsen, Torkjel Manning Sandanger, Therese Haugdahl Nøst, J. Ramón Quirós, Catalina Bonet, Miguel Rodríguez Barranco, María-Dolores Chirlaque, Eva Ardanaz, Malte Sandsveden, Jonas Manjer, Linda Vidman, Matilda Rentoft, David Muller, Kostas Tsilidis, Alicia K. Heath, Hector Keun, Jerzy Adamski, Pekka Keski-Rahkonen, Augustin Scalbert, Marc J. Gunter, Vivian Viallon, Cancer Research UK, Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Kræftens Bekæmpelse, DCS, Deutsches Krebsforschungszentrum, DKFZ, Centre International de Recherche sur le Cancer, CIRC: 2014/1183, C8221/A19170, Seventh Framework Programme, FP7: 2014/1193, 313010, C19335/A21351, National Research Council, NRC, World Cancer Research Fund International, WCRF, University of Maryland School of Public Health, SPH, Medical Research Council, MRC: MR/M012190/1, Cancer Research UK, CRUK: C8221/A29017, World Cancer Research Fund, WCRF, Imperial College London, European Commission, EC, Institut National de la Santé et de la Recherche Médicale, Inserm, Bundesministerium für Bildung und Forschung, BMBF, Cancerfonden, Generalitat de Catalunya, Ministerie van Volksgezondheid, Welzijn en Sport, VWS, Fondation ARC pour la Recherche sur le Cancer, ARC, Ligue Contre le Cancer, Vetenskapsrådet, VR, Instituto de Salud Carlos III, ISCIII, Associazione Italiana per la Ricerca sul Cancro, AIRC, Deutsche Krebshilfe, Institut National Du Cancer, INCa: 2009-139, 2013/1002, 2014-1-RT-02-CIRC-1, 2015-166, Institut Gustave-Roussy, Mutuelle Générale de l'Education Nationale, MGEN, Consejería de Salud y Familias, Junta de Andalucía, NIHR Imperial Biomedical Research Centre, BRC, The coordination of EPIC is financially supported by International Agency for Research on Cancer (IARC) and by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC)., This paper is dedicated to the memory our of colleague Dr. Bas Bueno-de-Mesquita. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization., The national cohorts are supported by Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France), German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany), Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and National Research Council (Italy), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands), Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology - ICO (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden), Cancer Research UK (14136 to EPIC-Norfolk, C8221/A29017 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (UK). IDIBELL acknowledges support from the Generalitat de Catalunya through the CERCA Program. The breast cancer study was funded by the French National Cancer Institute (grant number 2015-166). The colorectal cancer studies were funded by World Cancer Research Fund (reference: 2013/1002, reference: 313010, reference: 2014/1193, INCa, grant numbers 2009-139 and 2014-1-RT-02-CIRC-1) and by internal funds of the IARC. For the participants in the prostate cancer study, sample retrieval and preparation, and assays of metabolites were supported by Cancer Research UK (C8221/A19170), and funding for grant 2014/1183 was obtained from the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant programme. Mathilde His’ work reported here was undertaken during the tenure of a postdoctoral fellowship awarded by the International Agency for Research on Cancer, financed by the Fondation ARC. The funders were not involved in designing the study, collecting, analysing, and interpreting results, or writing and submitting the manuscript for publication., and HAL UVSQ, Équipe

Subjects
Male, Carcinoma, Hepatocellular, Proline, Glutamine, Kidney, Risk Factors, General & Internal Medicine, Humans, Metabolomics, Histidine, Prospective Studies, Breast, Càncer, 11 Medical and Health Sciences, Colorectal, Cancer, Cancer och onkologi, Liver Neoplasms, Prostate, Lysophosphatidylcholines, General Medicine, Sphingomyelins, Metabolòmica, Liver, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Case-Control Studies, Cancer and Oncology, Carcinoma, Hepatocellular/diagnosis, Phosphatidylcholines, Epic, Endometrial, Lasso, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, EPIC
Abstract

Background Epidemiological studies of associations between metabolites and cancer risk have typically focused on specific cancer types separately. Here, we designed a multivariate pan-cancer analysis to identify metabolites potentially associated with multiple cancer types, while also allowing the investigation of cancer type-specific associations. Methods We analysed targeted metabolomics data available for 5828 matched case-control pairs from cancer-specific case-control studies on breast, colorectal, endometrial, gallbladder, kidney, localized and advanced prostate cancer, and hepatocellular carcinoma nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. From pre-diagnostic blood levels of an initial set of 117 metabolites, 33 cluster representatives of strongly correlated metabolites and 17 single metabolites were derived by hierarchical clustering. The mutually adjusted associations of the resulting 50 metabolites with cancer risk were examined in penalized conditional logistic regression models adjusted for body mass index, using the data-shared lasso penalty. Results Out of the 50 studied metabolites, (i) six were inversely associated with the risk of most cancer types: glutamine, butyrylcarnitine, lysophosphatidylcholine a C18:2, and three clusters of phosphatidylcholines (PCs); (ii) three were positively associated with most cancer types: proline, decanoylcarnitine, and one cluster of PCs; and (iii) 10 were specifically associated with particular cancer types, including histidine that was inversely associated with colorectal cancer risk and one cluster of sphingomyelins that was inversely associated with risk of hepatocellular carcinoma and positively with endometrial cancer risk. Conclusions These results could provide novel insights for the identification of pathways for cancer development, in particular those shared across different cancer types.

Published
2022