Netherlands Translational Research Center B.V. | Date: 2017-02-15
The invention relates to a compound of Formula (I) wherein, R1 and R2 independently are selected from the group consisting of optionally substituted (6-10C)aryl and (1-5C)heteroaryl groups. The compounds can be used in pharmaceutical compositions, in particular in the treatment of cancer.
PubMed | University of Groningen and Netherlands Translational Research Center
Type: | Journal: Scientific reports | Year: 2016
The enzyme TDO (tryptophan 2,3-dioxygenase; TDO-2 in Caenorhabditis elegans) is a potential therapeutic target to cancer but is also thought to regulate proteotoxic events seen in the progression of neurodegenerative diseases. To better understand its function and develop specific compounds that target TDO we need to understand the structure of this molecule. In C. elegans we compared multiple different CRISPR/Cas9-induced tdo-2 deletion mutants and identified a motif of three amino acids (PLD) that is required for the enzymatic conversion of tryptophan to N-formylkynurenine. Loss of TDO-2s enzymatic activity in PDL deletion mutants was accompanied by an increase in motility during aging and a prolonged lifespan, which is in line with the previously observed phenotypes induced by a knockdown of the full enzyme. Comparison of sequence structures suggests that blocking this motif might interfere with haem binding, which is essential for the enzymes activity. The fact that these three residues are situated in an evolutionary conserved structural loop of the enzyme suggests that the findings can be translated to humans. The identification of this specific loop region in TDO-2-essential for its catalytic function-will aid in the design of novel inhibitors to treat diseases in which the TDO enzyme is overexpressed or hyperactive.
PubMed | Erasmus MC Rotterdam Sophia Childrens Hospital, Netherlands Translational Research Center and The Princess Maxima Center for Pediatric Oncology
Type: Journal Article | Journal: Leukemia | Year: 2016
We identified mutations in the IL7Ra gene or in genes encoding the downstream signaling molecules JAK1, JAK3, STAT5B, N-RAS, K-RAS, NF1, AKT and PTEN in 49% of patients with pediatric T-cell acute lymphoblastic leukemia (T-ALL). Strikingly, these mutations (except RAS/NF1) were mutually exclusive, suggesting that they each cause the aberrant activation of a common downstream target. Expressing these mutant signaling molecules-but not their wild-type counterparts-rendered Ba/F3 cells independent of IL3 by activating the RAS-MEK-ERK and PI3K-AKT pathways. Interestingly, cells expressing either IL7Ra or JAK mutants are sensitive to JAK inhibitors, but respond less robustly to inhibitors of the downstream RAS-MEK-ERK and PI3K-AKT-mTOR pathways, indicating that inhibiting only one downstream pathway is not sufficient. Here, we show that inhibiting both the MEK and PI3K-AKT pathways synergistically prevents the proliferation of BaF3 cells expressing mutant IL7Ra, JAK and RAS. Furthermore, combined inhibition of MEK and PI3K/AKT was cytotoxic to samples obtained from 6 out of 11 primary T-ALL patients, including 1 patient who had no mutations in the IL7R signaling pathway. Taken together, these results suggest that the potent cytotoxic effects of inhibiting both MEK and PI3K/AKT should be investigated further as a therapeutic option using leukemia xenograft models.
Maia A.R.R.,Netherlands Cancer Institute |
De Man J.,Netherlands Translational Research Center |
Boon U.,Netherlands Cancer Institute |
Janssen A.,Netherlands Cancer Institute |
And 14 more authors.
Annals of Oncology | Year: 2015
Background: Triple-negative breast cancers (TNBC) are considered the most aggressive type of breast cancer, for which no targeted therapy exists at the moment. These tumors are characterized by having a high degree of chromosome instability and often overexpress the spindle assembly checkpoint kinase TTK. To explore the potential of TTK inhibition as a targeted therapy in TNBC, we developed a highly potent and selective small molecule inhibitor of TTK, NTRC 0066-0. Results and Conclusions: The compound is characterized by long residence time on the target and inhibits the proliferation of a wide variety of human cancer cell lines with potency in the same range as marketed cytotoxic agents. In cell lines and in mice, NTRC 0066-0 inhibits the phosphorylation of a TTK substrate and induces chromosome missegregation. NTRC 0066-0 inhibits tumor growth in MDA-MB-231 xenografts as a single agent after oral application. To address the effect of the inhibitor in breast cancer, we used a well-defined mouse model that spontaneously develops breast tumors that share key morphologic and molecular features with human TNBC. Our studies show that combination of NTRC 0066-0 with a therapeutic dose of docetaxel resulted in doubling of mouse survival and extended tumor remission, without toxicity. Furthermore, we observed that treatment efficacy is only achieved upon co-administration of the two compounds, which suggests a synergistic in vivo effect. Therefore, we propose TTK inhibition as a novel therapeutic target for neoadjuvant therapy in TNBC. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.
van der Lee M.M.C.,Merck And Co. |
Verkaar F.,VU University Amsterdam |
Wat J.W.Y.,Merck And Co. |
van Offenbeek J.,VU University Amsterdam |
And 6 more authors.
Cellular Signalling | Year: 2013
Parathyroid hormone (PTH) is an anabolic agent that mediates bone formation through activation of the Gαs-, Gαq- and β-arrestin-coupled parathyroid hormone receptor type 1 (PTH1R). Pharmacological evidence based on the effect of PTH(7-34), a PTH derivative that is said to preferentially activate β-arrestin signaling through PTH1R, suggests that PTH1R-activated β-arrestin signaling mediates anabolic effects on bone. Here, we performed a thorough evaluation of PTH(7-34) signaling behaviour using quantitative assays for β-arrestin recruitment, Gαs- and Gαq-signaling. We found that PTH(7-34) inhibited PTH-induced cAMP accumulation, but was unable to induce β-arrestin recruitment, PTH1R internalization and ERK1/2 phosphorylation in HEK293, CHO and U2OS cells. Thus, the β-arrestin bias of PTH(7-34) is not apparent in every cell type examined, suggesting that correlating in vivo effects of PTH(7-34) to in vitro pharmacology should be done with caution. © 2012 Elsevier Inc.
Agency: European Commission | Branch: FP7 | Program: MC-ITN | Phase: FP7-PEOPLE-2013-ITN | Award Amount: 3.02M | Year: 2013
Aneuploidy, an abnormal number of chromosomes, is a hallmark of cancer cells, affecting the majority of all human tumours. Aneuploidy arises when errors occur during mitosis, as the duplicated chromosomes are distributed between the two new daughter cells. Paradoxically, aneuploidy appears to have detrimental consequences for the physiology of untransformed cells in vitro, inhibiting rather than stimulating proliferation. This suggests that cancer cells have acquired mutations that help them cope with aneuploidy. Although it is clear that aneuploidy can contribute to cancer, the molecular consequences of aneuploidy remain elusive, as does how aneuploidy contributes to malignant transformation. The scientific aim of this network is to determine and compare the molecular consequences of different levels of aneuploidy, both in vivo and in vitro. Our network will train 9 Early Stage Career and 2 Experienced researchers in the aneuploidy field. To this aim, we are combining the expertise of labs that study the causes of aneuploidy with labs that induce aneuploidy in model organisms and study its consequences and also with labs that focus on the development of therapeutics that selectively kill aneuploid cell progeny. Our network is comprised of 11 full participants in 4 member states and 1 associated country and one associated partner, and includes 3 commercial enterprises. Within this network, we will provide technical training through research projects, but also through workshops and dedicated courses organized by the participants of this network. A significant part of the training will be provided by the industrial partners. Participating investigators and trainees will meet at a yearly conference to exchange and discuss results. Trainees will thus become experts in the field of aneuploidy while rapidly building up a scientific network for themselves, putting them in an excellent position to become future leaders in this field.
Agency: European Commission | Branch: H2020 | Program: SME-1 | Phase: PHC-12-2014-1 | Award Amount: 71.43K | Year: 2015
The lack of clinically validated biomarkers to properly select patients for treatment with anti-cancer agents remains a major problem. Patients are not always receiving the most optimal treatment, resulting in poor response rates and high societal costs. By profiling more than hundred drugs on a broad panel of genetically characterized cell lines, researchers from NTRC have identified novel predictive drug response biomarkers for several anti-cancer agents. In the feasibility (Phase 1) study two of these genomic drug sensitivity markers will be validated using whole genome sequencing data of patients treated with the corresponding agents. In addition, a protein kinase that is involved in glucocorticoid resistance in T-cell leukemia will be validated. Proliferation assays will be carried out with blood samples from leukemia patients using proprietary inhibitors that NTRC has developed against this kinase. After successful completion of Phase 1, the project will be extended to other drug sensitivity markers identified by cancer cell line profiling in Phase 2 of the project. In addition, assays to determine the mutant status of cancer genes in circulating DNA and miniaturized proliferation assays with patient blood cells will be developed. In the commercialization phase of the project, novel clinically validated biomarkers and assays for several anti-cancer drugs will be licensed to pharmaceutical and diagnostic companies. The results of the feasibility project will increase the value of NTRCs biomarker discovery platform, resulting in a doubling of turn-over within two years. In addition, novel IP will be generated and licensed to pharmaceutical and diagnostic companies. After six years an ROI of seven times the initial investment is estimated. Overall, the project will result in increased clinical availability of genomic biomarkers, contribute to an overall improvement of cancer therapy, and increased sustainability of health care systems in the EU.
PubMed | Netherlands Translational Research Center
Type: Journal Article | Journal: PloS one | Year: 2015
The aim of combination drug treatment in cancer therapy is to improve response rate and to decrease the probability of the development of drug resistance. Preferably, drug combinations are synergistic rather than additive, and, ideally, drug combinations work synergistically only in cancer cells and not in non-malignant cells. We have developed a workflow to identify such targeted synergies, and applied this approach to selectively inhibit the proliferation of cell lines with mutations in genes that are difficult to modulate with small molecules. The approach is based on curve shift analysis, which we demonstrate is a more robust method of determining synergy than combination matrix screening with Bliss-scoring. We show that the MEK inhibitor trametinib is more synergistic in combination with the BRAF inhibitor dabrafenib than with vemurafenib, another BRAF inhibitor. In addition, we show that the combination of MEK and BRAF inhibitors is synergistic in BRAF-mutant melanoma cells, and additive or antagonistic in, respectively, BRAF-wild type melanoma cells and non-malignant fibroblasts. This combination exemplifies that synergistic action of drugs can depend on cancer genotype. Next, we used curve shift analysis to identify new drug combinations that specifically inhibit cancer cell proliferation driven by difficult-to-drug cancer genes. Combination studies were performed with compounds that as single agents showed preference for inhibition of cancer cells with mutations in either the CTNNB1 gene (coding for -catenin), KRAS, or cancer cells expressing increased copy numbers of MYC. We demonstrate that the Wnt-pathway inhibitor ICG-001 and trametinib acted synergistically in Wnt-pathway-mutant cell lines. The ERBB2 inhibitor TAK-165 was synergistic with trametinib in KRAS-mutant cell lines. The EGFR/ERBB2 inhibitor neratinib acted synergistically with the spindle poison docetaxel and with the Aurora kinase inhibitor GSK-1070916 in cell lines with MYC amplification. Our approach can therefore efficiently discover novel drug combinations that selectively target cancer genes.
PubMed | Netherlands Translational Research Center and Carna Biosciences Inc.
Type: | Journal: Journal of molecular biology | Year: 2017
Target residence time () has been suggested to be a better predictor of the biological activity of kinase inhibitors than inhibitory potency (IC
News Article | December 20, 2016
In the third week of PLOS Medicine's ongoing special issue on cancer genomics, principal investigator Jules Meijerink of the Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands and colleagues seek to identify mechanisms underlying treatment resistance in children with T-cell acute lymphoblastic leukemia (T-ALL) by combining genomic DNA sequencing and chromosomal copy-number analyses, and suggest a new approach to therapy. Treatment of childhood leukemia has improved markedly in recent decades, with long-term cure achieved in most patients who have access to modern, highly intensive treatment regimens. However, some patients develop resistance to the steroid drugs which are a key part of combination chemotherapy treatments, which results in poor clinical outcomes. As described in their Research Article, Meijerink and colleagues studied genetic changes in leukemic cells from pediatric T-ALL patients before treatment. The researchers found specific gene mutations affecting signaling inside cells, involving the interleukin 7 receptor and downstream molecules, that were associated with steroid resistance and adverse clinical outcome. Drugs designed to target individual signaling proteins were able to restore steroid sensitivity to primary leukemic cells from patients. Discussing the research in an accompanying Perspective article, Steven Goossens and Pieter Van Vlierberghe conclude that "inhibition of MEK-ERK or PI3K/AKT/mTOR signaling could enhance steroid sensitivity in T-ALL and potentially improve patient outcomes, a notion that warrants investigation in future prospective clinical trials." Funding: YL was funded by Stichting Kinderen Kankervrij (https:/ ; KiKa-2010-082). KC-B and WKS were funded by Stichting Kinderen Kankervrij (https:/ ; KiKa-2008-029, KiKa-2013-116). EMV was funded by KWF Kanker Bestrijding (https:/ ; EMCR-KWF-2010-4691). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: RCB and GJRZ are founders and shareholders of Netherlands Translational Research Center B.V. The other authors have declared that no competing interests exist. Citation: Li Y, Buijs-Gladdines JGCAM, Canté-Barrett K, Stubbs AP, Vroegindeweij EM, Smits WK, et al. (2016) IL-7 Receptor Mutations and Steroid Resistance in Pediatric T cell Acute Lymphoblastic Leukemia: A Genome Sequencing Study. PLoS Med 13(12): e1002200. doi:10.1371/journal.pmed.1002200 Author Affiliations: Department of Pediatric Oncology/Hematology, Erasmus Medical Center/Sophia Children's Hospital, Rotterdam, The Netherlands Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands Department of Bioinformatics, Erasmus Medical Center, Rotterdam, The Netherlands Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands Research Institute Children's Cancer Center Hamburg, Hamburg, Germany Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Co-operative Study Group for Childhood Acute Lymphoblastic Leukemia, Hamburg, Germany Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands Netherlands Translational Research Center, Oss, The Netherlands IN YOUR COVERAGE PLEASE USE THIS URL TO PROVIDE ACCESS TO THE FREELY AVAILABLE PAPER: http://journals. Funding: The authors received no funding for this work. Competing Interests: The authors have declared that no competing interests exist. IN YOUR COVERAGE PLEASE USE THIS URL TO PROVIDE ACCESS TO THE FREELY AVAILABLE PAPER: http://journals.