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Pallis M.,University of Nottingham | Burrows F.,Tragara Pharmaceuticals | Ryan J.,Harvard University | Grundy M.,University of Nottingham | And 5 more authors.
Oncotarget | Year: 2017

Direct co-operation between sensitiser molecules BAD and NOXA in mediating apoptosis suggests that therapeutic agents which sensitise to BAD may complement agents which sensitise to NOXA. Dynamic BH3 profiling is a novel methodology that we have applied to the measurement of complementarity between sensitiser BH3 peptide mimetics and therapeutic agents. Using dynamic BH3 profiling, we show that the agent TG02, which downregulates MCL-1, sensitises to the BCL-2-inhibitory BADBH3 peptide, whereas the BCL-2 antagonist ABT-199 sensitises to MCL-1 inhibitory NOXA-BH3 peptide in acute myeloid leukaemia (AML) cells. At the concentrations used, the peptides did not trigger mitochondrial outer membrane permeabilisation in their own right, but primed cells to release Cytochrome C in the presence of an appropriate trigger of a complementary pathway. In KG-1a cells TG02 and ABT-199 synergised to induce apoptosis. In heterogeneous AML patient samples we noted a range of sensitivities to the two agents. Although some individual samples markedly favoured one agent or the other, in the group as a whole the combination of TG02 + ABT-199 was significantly more cytotoxic than either agent individually. We conclude that dynamic NOXA and BAD BH3 profiling is a sensitive methodology for investigating molecular pathways of drug action and complementary mechanisms of chemoresponsiveness.


— Chronic Lymphocytic Leukemia (CLL) Pipeline Market Companies Involved in Therapeutics Development are 4SC AG, AbbVie Inc, Acetylon Pharmaceuticals Inc, Aeglea BioTherapeutics Inc, Altor BioScience Corp, Amgen Inc, Aprea AB, Aptevo Therapeutics Inc, Arno Therapeutics Inc, ArQule Inc, Astellas Pharma Inc, Astex Pharmaceuticals Inc, Baliopharm AG, Bayer AG, BeiGene Ltd, Bellicum Pharmaceuticals Inc, Biogen Inc, Bionomics Ltd, Bionovis SA, Biothera Pharmaceutical Inc, Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company, Celgene Corp, Cellectis SA, Cellular Biomedicine Group Inc, Coherus BioSciences Inc, CrystalGenomics Inc, Cyclacel Pharmaceuticals Inc, Daiichi Sankyo Company Ltd, Eli Lilly and Company, F. Hoffmann-La Roche Ltd, GeneaMed Ltd, Genentech Inc, Genor BioPharma Co Ltd, Gilead Sciences Inc, Grupo Ferrer Internacional SA, Hutchison MediPharma Ltd, Hybrigenics SA, Igenica Biotherapeutics Inc, Immatics Biotechnologies GmbH, ImmunoGen Inc, Immunomedics Inc, Incyte Corp, Inflection Biosciences Ltd, Innate Pharma SA, Innovent Biologics Inc, Johnson & Johnson, Juno Therapeutics Inc, Kancera AB, Karyopharm Therapeutics Inc, Kite Pharma Inc, Les Laboratoires Servier SAS, LFB SA, Lymphocyte Activation Technologies SA, Medicenna Therapeutics Inc, MENTRIK Biotech LLC, Merck & Co Inc, Merck KGaA, Mesoblast Ltd, Millennium Pharmaceuticals Inc, MorphoSys AG, NantKwest Inc, Nordic Nanovector ASA, Novartis AG, Oncternal Therapeutics, Inc., Ono Pharmaceutical Co Ltd, Panacea Biotec Ltd, PEP-Therapy SAS, Pfizer Inc, Pharmacyclics Inc, PIQUR Therapeutics AG, Portola Pharmaceuticals Inc, Redx Pharma Plc, Respiratorius AB, Revitope Oncology, Inc., Rhizen Pharmaceuticals SA, Sandoz International GmbH, Sanofi, Selvita SA, Simcere Pharmaceutical Group, Sorrento Therapeutics Inc, Supratek Pharma Inc, Takeda Pharmaceutical Company Ltd, Targazyme Inc, TG Therapeutics Inc, The International Biotechnology Center (IBC) Generium, Theravectys SA, Tolero Pharmaceuticals Inc, TRACON Pharmaceuticals Inc, Tragara Pharmaceuticals Inc, Trillium Therapeutics Inc, United BioPharma, Inc., Unum Therapeutics Inc, Verastem Inc, VioQuest Pharmaceuticals Inc, Viralytics Ltd, Xencor Inc, ZIOPHARM Oncology Inc and Zymeworks Inc. This research provides comprehensive information on the therapeutics under development for Chronic Lymphocytic Leukemia (CLL) (Oncology), complete with analysis by stage of development, drug target, mechanism of action (MoA), route of administration (RoA) and molecule type. The guide covers the descriptive pharmacological action of the therapeutics, its complete research and development history and latest news and press releases. Inquire more about this research report at http://www.reportsnreports.com/contacts/inquirybeforebuy.aspx?name=774108 The Chronic Lymphocytic Leukemia (CLL) (Oncology) pipeline guide also reviews of key players involved in therapeutic development for Chronic Lymphocytic Leukemia (CLL) and features dormant and discontinued projects. The guide covers therapeutics under Development by Companies /Universities /Institutes, the molecules developed by Companies in Pre-Registration, Phase III, Phase II, Phase I, Phase 0, IND/CTA Filed, Preclinical, Discovery and Unknown stages are 5, 5, 43, 45, 1, 3, 54, 13 and 1 respectively. Similarly, the Universities portfolio in Phase II, Phase I, Preclinical and Discovery stages comprises 4, 6, 8 and 7 molecules, respectively. Chronic Lymphocytic Leukemia (CLL) (Oncology) pipeline guide helps in identifying and tracking emerging players in the market and their portfolios, enhances decision making capabilities and helps to create effective counter strategies to gain competitive advantage. The guide is built using data and information sourced from Global Markets Directs proprietary databases, company/university websites, clinical trial registries, conferences, SEC filings, investor presentations and featured press releases from company/university sites and industry-specific third party sources. Additionally, various dynamic tracking processes ensure that the most recent developments are captured on a real time basis. Note: Certain content / sections in the pipeline guide may be removed or altered based on the availability and relevance of data. Buy a copy of this research report at http://www.reportsnreports.com/purchase.aspx?name=774108 • The pipeline guide provides a snapshot of the global therapeutic landscape of Chronic Lymphocytic Leukemia (CLL) (Oncology). • The pipeline guide reviews pipeline therapeutics for Chronic Lymphocytic Leukemia (CLL) (Oncology) by companies and universities/research institutes based on information derived from company and industry-specific sources. • The pipeline guide covers pipeline products based on several stages of development ranging from pre-registration till discovery and undisclosed stages. • The pipeline guide features descriptive drug profiles for the pipeline products which comprise, product description, descriptive licensing and collaboration details, R&D brief, MoA & other developmental activities. • The pipeline guide reviews key companies involved in Chronic Lymphocytic Leukemia (CLL) (Oncology) therapeutics and enlists all their major and minor projects. • The pipeline guide evaluates Chronic Lymphocytic Leukemia (CLL) (Oncology) therapeutics based on mechanism of action (MoA), drug target, route of administration (RoA) and molecule type. • The pipeline guide encapsulates all the dormant and discontinued pipeline projects. • The pipeline guide reviews latest news related to pipeline therapeutics for Chronic Lymphocytic Leukemia (CLL) (Oncology) • Procure strategically important competitor information, analysis, and insights to formulate effective R&D strategies. • Recognize emerging players with potentially strong product portfolio and create effective counter-strategies to gain competitive advantage. • Find and recognize significant and varied types of therapeutics under development for Chronic Lymphocytic Leukemia (CLL) (Oncology). • Classify potential new clients or partners in the target demographic. • Develop tactical initiatives by understanding the focus areas of leading companies. • Plan mergers and acquisitions meritoriously by identifying key players and it’s most promising pipeline therapeutics. • Formulate corrective measures for pipeline projects by understanding Chronic Lymphocytic Leukemia (CLL) (Oncology) pipeline depth and focus of Indication therapeutics. • Develop and design in-licensing and out-licensing strategies by identifying prospective partners with the most attractive projects to enhance and expand business potential and scope. • Adjust the therapeutic portfolio by recognizing discontinued projects and understand from the know-how what drove them from pipeline. For more information, please visit http://www.reportsnreports.com/reports/774108-chronic-lymphocytic-leukemia-cll-pipeline-review-h2-2016.html


Ortiz-Ruiz M.J.,University of Salamanca | Alvarez-Fernandez S.,University of Salamanca | Parrott T.,Tragara Pharmaceuticals | Zaknoen S.,Tragara Pharmaceuticals | And 4 more authors.
Oncotarget | Year: 2014

Triple negative breast cancers (TNBCs) account for 15% of all breast cancers, and represent one of the most aggressive forms of the disease, exhibiting short relapse-free survival. In contrast to other breast cancer subtypes, the absence of knowledge about the etiopathogenic alterations that cause TNBCs force the use of chemotherapeutics to treat these tumors. Because of this, efforts have been devoted with the aim of incorporating novel therapies into the clinical setting. Kinases play important roles in the pathophysiology of several tumors, including TNBC. Since expression of the MAP kinase ERK5 has been linked to patient outcome in breast cancer, we analyzed the potential value of its targeting in TNBC. ERK5 was frequently overexpressed and active in samples from patients with TNBC, as well as in explants from mice carrying genetically-defined TNBC tumors. Moreover, expression of ERK5 was linked to a worse prognosis in TNBC patients. Knockdown experiments demonstrated that ERK5 supported proliferation of TNBC cells. Pharmacological inhibition of ERK5 with TG02, a clinical stage inhibitor which targets ERK5 and other kinases, inhibited cell proliferation by blocking passage of cells through G1 and G2, and also triggered apoptosis in certain TNBC cell lines. TG02 had significant antitumor activity in a TNBC xenograft model in vivo, and also augmented the activity of chemotherapeutic agents commonly used to treat TNBC. Together, these data indicate that ERK5 targeting may represent a valid strategy against TNBC, and support the development of trials aimed at evaluating the clinical effectiveness of drugs that block this kinase.


Alvarez-Fernandez S.,University of Salamanca | Ortiz-Ruiz M.J.,University of Salamanca | Parrott T.,Tragara Pharmaceuticals | Zaknoen S.,Tragara Pharmaceuticals | And 7 more authors.
Clinical Cancer Research | Year: 2013

Purpose: To analyze the antimyeloma potential of TG02, an ERK5/CDK inhibitory drug. Experimental Design: Utilizing different multiple myeloma cell lines we determined the effect of TG02 over viability by MTT assays. The apoptotic effect over multiple myeloma patient samples was studied ex vivo by cytometry. The mechanism of action of TG02 was analyzed in the cell line MM1S, studying its effect on the cell cycle, the induction of apoptosis, and the loss of mitochondrial membrane potential by cytometry and Western blot. Two models of multiple myeloma xenograft were utilized to study the in vivo action of TG02. Results: TG02 potently inhibited proliferation and survival of multiple myeloma cell lines, even under protective bone marrow niche conditions, and selectively induced apoptosis of primary patient-derived malignant plasma cells. TG02 displayed significant single-agent activity in two multiple myeloma xenograft models, and enhanced the in vivo activity of bortezomib and lenalidomide. Signaling analyses revealed that the drug simultaneously blocked the activity of CDKs 1, 2, and 9 as well as the MAP kinase ERK5 in MM1S cells, leading to cell-cycle arrest and rapid commitment to apoptosis. TG02 induced robust activation of both the intrinsic and extrinsic pathways of apoptosis, and depletion of XIAP and the key multiple myeloma survival protein Mcl-1. Conclusions: TG02 is a promising new antimyeloma agent that is currently in phase I clinical trials in leukemia and multiple myeloma patients. © 2013 AACR.


PubMed | Tragara Pharmaceuticals, Hospital Universitario Of Albacete And Aecc Unit and University of Salamanca
Type: Journal Article | Journal: Oncotarget | Year: 2014

Triple negative breast cancers (TNBCs) account for 15% of all breast cancers, and represent one of the most aggressive forms of the disease, exhibiting short relapse-free survival. In contrast to other breast cancer subtypes, the absence of knowledge about the etiopathogenic alterations that cause TNBCs force the use of chemotherapeutics to treat these tumors. Because of this, efforts have been devoted with the aim of incorporating novel therapies into the clinical setting. Kinases play important roles in the pathophysiology of several tumors, including TNBC. Since expression of the MAP kinase ERK5 has been linked to patient outcome in breast cancer, we analyzed the potential value of its targeting in TNBC. ERK5 was frequently overexpressed and active in samples from patients with TNBC, as well as in explants from mice carrying genetically-defined TNBC tumors. Moreover, expression of ERK5 was linked to a worse prognosis in TNBC patients. Knockdown experiments demonstrated that ERK5 supported proliferation of TNBC cells. Pharmacological inhibition of ERK5 with TG02, a clinical stage inhibitor which targets ERK5 and other kinases, inhibited cell proliferation by blocking passage of cells through G1 and G2, and also triggered apoptosis in certain TNBC cell lines. TG02 had significant antitumor activity in a TNBC xenograft model in vivo, and also augmented the activity of chemotherapeutic agents commonly used to treat TNBC. Together, these data indicate that ERK5 targeting may represent a valid strategy against TNBC, and support the development of trials aimed at evaluating the clinical effectiveness of drugs that block this kinase.


Goh K.C.,SBIO Pte Ltd | Novotny-Diermayr V.,SBIO Pte Ltd | Hart S.,SBIO Pte Ltd | Ong L.C.,SBIO Pte Ltd | And 12 more authors.
Leukemia | Year: 2012

TG02 is a novel pyrimidine-based multi-kinase inhibitor that inhibits CDKs 1, 2, 7 and 9 together with JAK2 and FLT3. It dose-dependently inhibits signaling pathways downstream of CDKs, JAK2 and FLT3 in cancer cells with the main targets being CDKs. TG02 is anti-proliferative in a broad range of tumor cell lines, inducing G1 cell cycle arrest and apoptosis. Primary cultures of progenitor cells derived from acute myeloid leukemia (AML) and polycythemia vera patients are very sensitive to TG02. Comparison with reference inhibitors that block only one of the main targets of TG02 demonstrate the benefit of combined CDK and JAK2/FLT3 inhibition in cell lines as well as primary cells. In vivo, TG02 exhibits favorable pharmacokinetics after oral dosing in xenograft models and accumulates in tumor tissues, inducing an effective blockade of both CDK and STAT signaling. TG02 induces tumor regression after oral dosing on both daily and intermittent schedules in a murine model of mutant-FLT3 leukemia (MV4-11) and prolongs survival in a disseminated AML model with wild-type FLT3 and JAK2 (HL-60). These data demonstrate that TG02 is active in various models of leukemia and provide a rationale for the ongoing clinical evaluation of TG02 in patients with advanced leukemias. © 2012 Macmillan Publishers Limited All rights reserved.

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