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Martin L.J.,Johns Hopkins University | Fancelli D.,Genextra | Wong M.,Johns Hopkins University | Niedzwiecki M.,Johns Hopkins University | And 3 more authors.
Frontiers in Cellular Neuroscience | Year: 2014

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder in humans characterized by progressive degeneration of skeletal muscle and motor neurons in spinal cord, brainstem, and cerebral cortex causing skeletal muscle paralysis, respiratory insufficiency, and death. There are no cures or effective treatments for ALS. ALS can be inherited, but most cases are not associated with a family history of the disease. Mitochondria have been implicated in the pathogenesis but definitive proof of causal mechanisms is lacking. Identification of new clinically translatable disease mechanism-based molecular targets and small molecule drug candidates are needed for ALS patients. We tested the hypothesis in an animal model that drug modulation of the mitochondrial permeability transition pore (mPTP) is therapeutic in ALS. A prospective randomized placebo-controlled drug trial was done in a transgenic (tg) mouse model of ALS. We explored GNX-4728 as a therapeutic drug. GNX-4728 inhibits mPTP opening as evidenced by increased mitochondrial calcium retention capacity (CRC) both in vitro and in vivo. Chronic systemic treatment of G37R-human mutant superoxide dismutase-1 (hSOD1) tg mice with GNX-4728 resulted in major therapeutic benefits. GNX-4728 slowed disease progression and significantly improved motor function. The survival of ALS mice was increased significantly by GNX-4728 treatment as evidence by a nearly 2-fold extension of lifespan (360 days–750 days). GNX-4728 protected against motor neuron degeneration and mitochondrial degeneration, attenuated spinal cord inflammation, and preserved neuromuscular junction (NMJ) innervation in the diaphragm in ALS mice. This work demonstrates that a mPTP-acting drug has major disease-modifying efficacy in a preclinical mouse model of ALS and establishes mitochondrial calcium retention, and indirectly the mPTP, as targets for ALS drug development. © 2014, Frontiers Research Foundation. All rights reserved.


Albanese C.,BU Oncology | Alzani R.,BU Oncology | Amboldi N.,BU Oncology | Degrassi A.,BU Oncology | And 9 more authors.
British Journal of Pharmacology | Year: 2013

Background and Purpose Malignant gliomas, the most common primary brain tumours, are highly invasive and neurologically destructive neoplasms with a very bad prognosis due to the difficulty in removing the mass completely by surgery and the limited activity of current therapeutic agents. PHA-848125 is a multi-kinase inhibitor with broad anti-tumour activity in pre-clinical studies and good tolerability in phase 1 studies, which could affect two main pathways involved in glioma pathogenesis, the G1-S phase progression control pathway through the inhibition of cyclin-dependent kinases and the signalling pathways mediated by tyrosine kinase growth factor receptors, such as tropomyosin receptors. For this reason, we tested PHA-848125 in glioma models. Experimental Approach PHA-848125 was tested on a panel of glioma cell lines in vitro to evaluate inhibition of proliferation and mechanism of action. In vivo efficacy was evaluated on two glioma models both as single agent and in combination with standard therapy. Key Results When tested on a subset of representative glioma cell lines, PHA-848125 blocked cell proliferation, DNA synthesis and inhibited both cell cycle and signal transduction markers. Relevantly, PHA-848125 was also able to induce cell death through autophagy in all cell lines. Good anti-tumour efficacy was observed by oral route in different glioma models both with s.c. and intracranial implantation. Indeed, we demonstrate that the drug is able to cross the blood-brain barrier. Moreover, the combination of PHA-848125 with temozolomide resulted in a synergistic effect, and a clear therapeutic gain was also observed with a triple treatment adding PHA-848125 to radiotherapy and temozolomide. Conclusions and Implications All the pre-clinical data obtained so far suggest that PHA-848125 may become a useful agent in chemotherapy regimens for glioma patients and support its evaluation in phase 2 trials for this indication. © 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society.


Mercurio C.,Genextra | Minucci S.,IFOM IEO Campus | Minucci S.,University of Milan | Pelicci P.G.,IFOM IEO Campus | Pelicci P.G.,University of Milan
Pharmacological Research | Year: 2010

Histone deacetylase inhibitors (HDACi) represent a novel class of targeted drugs which alter the acetylation status of several cellular proteins. These agents, modulating both chromatin structure through histone acetylation, and the activity of several non-histone substrates, are at the same time able to determine changes in gene transcription and to induce a plethora of biological effects ranging from cell death induction, to differentiation, angiogenesis inhibition or modulation of immune responses. The impressive anticancer activity observed in both in vitro and in vivo cancer models, together with their preferential effect on cancer cells, have led to a huge effort into the identification and development of HDACi with different characteristics.To date, several clinical trials of HDACi conducted in solid tumors and hematological malignancies have shown a preferential clinical efficacy of these drugs in hematological malignancies, and in particular in cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), Hodgkin lymphoma (HL) and myeloid malignancies.Several agents are also beginning to be tested in combination therapies, either as chemo sensitizing agents in association with standard chemotherapy drugs or in combination with DNA methyltransferase inhibitors (DNMTi) in the context of the so-called " epigenetic therapies" , aimed to revert epigenetic alterations found in cancer cells. Herein, we will review HDACi data in hematological malignancies questioning the molecular basis of observed clinical responses, and highlighting some of the concerns raised on the use of these drugs for cancer therapy. © 2010 Elsevier Ltd.


News Article | November 9, 2016
Site: www.newsmaker.com.au

The report provides comprehensive information on the therapeutics under development for Basal Cell Carcinoma (Basal Cell Epithelioma) ,complete with analysis by stage of development,drug target,mechanism of action (MoA),route of administration (RoA) and molecule type. The report also coversthe descriptive pharmacological action of the therapeutics,its complete research and development history and latest news and press releases. Additionally,the report provides an overview of key players involved in therapeutic development for Basal Cell Carcinoma (Basal Cell Epithelioma)  and features dormant and discontinued projects. The report 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. Complete report on Basal Cell Carcinoma (Basal Cell Epithelioma)  - Pipeline Review,H2 2016 addition with 27 market data tables and 12 figures, spread across 112 pages is available at http://www.rnrmarketresearch.com/basal-cell-carcinoma-basal-cell-epithelioma-pipeline-review-h2-2016-market-report.html This report features investigational drugs from across globe covering over 20 therapy areas and nearly 3,000 indications. The report is built using data and information sourced from Global Markets Direct's 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. Drug profiles featured in the report undergoes periodic review following a stringent set of processes to ensure that all the profiles are updated with the latest set of information. Additionally,various dynamic tracking processes ensure that the most recent developments are captured on a real time basis. Biofrontera AG,Biosceptre (Aust) Pty Ltd,Cannabis Science, Inc,Genextra S.p.a.,Ignyta, Inc. Laboratories Ojer Pharma S.L.,MediGene AG,Merck & Co., Inc.,PellePharm, Inc.,Provectus Biopharmaceuticals, Inc.,Redx Pharma Plc,Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd.,Transgene SA Inquire before buying  http://www.rnrmarketresearch.com/contacts/inquire-before-buying?rname=748017(This is a premium report price at US$2000 for a single user PDF license).


News Article | December 20, 2016
Site: globenewswire.com

Dublin, Dec. 20, 2016 (GLOBE NEWSWIRE) -- Research and Markets has announced the addition of the "HDAC Inhibitors Market, 2016 - 2026" report to their offering. The HDAC Inhibitors Market, 2016-2026 report was commissioned to examine the current landscape and the future outlook of the growing pipeline of products in this area. HDACs have been studied in cellular processes such as apoptosis, autophagy, metabolism, DNA damage repair, cell cycle control and senescence. Altered expression of HDACs has been observed in different tumors; this makes them a potential target for treatment of cancer and other genetic or epigenetic related disorders. Inhibition of HDACs has shown positive results in disruption of multiple cell signaling pathways and prevention of tumor growth. The study provides a detailed market forecast and opportunity analysis for the time period 2016-2026. The research, analysis and insights presented in this report include potential sales of the approved drugs and the ones in late stages of development (phase III and phase II). To add robustness to our model, we have provided three scenarios for our market forecast; these include the conservative, base and optimistic scenarios. Our opinions and insights, presented in this study were influenced by several discussions we conducted with experts in this area. All actual figures have been sourced and analyzed from publicly available information forums and primary research discussions. Financial figures mentioned in this report are in USD, unless otherwise specified. Example Highlights - Nearly 90 HDAC inhibitors are currently in clinical / preclinical stages of development; the clinical molecules account for over 30% of the pipeline while over 60% is captured by molecules in the preclinical / discovery stage. - With 66% of the pipeline molecules targeting oncological indications, cancer remains one of the most widely studied field for HDAC inhibitors. Within oncology, hematological malignancies such as PTCL and CTCL are popular targets; three HDAC inhibitors (Zolinza, ISTODAX® and BELEODAQ®) are approved for these indications. Other therapeutic areas such as autoimmune disorders, infectious diseases, inflammatory disorders, neurological disorders, are also gradually gaining traction. - Although the market was initially led by the large-size pharma players (such as Celgene, Merck, Novartis), the current market is characterized by the presence of several small / mid-sized pharma players. Notable examples of the small and mid-sized firms include 4SC, Chroma Therapeutics, CrystalGenomics, Curis, Evgen Pharma, FORUM Pharmaceuticals, Karus Therapeutics, Mirati Therapeutics, MEI Pharma, Shenzhen Chipscreen Biosciences, Syndax Pharmaceuticals and TetraLogic Pharmaceuticals. - In addition, there are several non-industry institutes and universities that are primarily carrying out preclinical research. Examples of these include Harvard Medical School (BG45), Imperial College London (C1A), Kyoto University (Jd, Sd), National Taiwan University (Quinazolin-4-one derivatives), Taipei Medical University (MPT0E028), University of Messina (MC-1575, MC-1568). - Four of the five approved drugs are pan-HDAC inhibitors targeting HDAC isoforms non-specifically. However, in the past few years, several class selective HDAC inhibitors have entered the clinic; these are associated with a higher efficacy and result in decreased toxicity from the treatment. Of the total HDAC inhibitors identified, 52% of the molecules are class specific; of these, 33% molecules target Class I specific isoforms and the rest target Class II specific isoforms of HDACs. Notable examples of molecules targeting class-specific HDACs includeentinostat (phase III), resminostat (phase II), SHP-141 (phase II), mocetinostat (phase II), CHR-3996 (phase I/II) and ricolinostat (phase I/II). - The HDAC inhibitors market is expected to grow at a healthy annual rate of 32% over the next decade.With multiple potential target indications, Istodax® is expected to capture the largest market share (close to 21%) in 2026, followed by entinostat, Farydak® and Beleodaq®. Key Topics Covered: 1. Preface 1.1. Scope Of The Report 1.2. Research Methodology 1.3. Chapter Outlines 2. Executive Summary 3. Introduction 3.1. The Central Dogma of Molecular Biology and Cell Cycle 3.2. DNA: Structure and Functions 3.3. Fundamentals of Epigenetics 3.3.1. Effect of Histone Modification on DNA Based Processes 3.3.2. Chromatin Structure Modification and its Enzymes 3.4. Histone Deacetylases (HDACs) 3.4.1. Classification of HDACs 3.4.2. Role of HDACs and HDAC Inhibitors in Cellular Processes 3.5. HDAC Inhibitors 3.5.1. Structure and Classification 3.5.2. Different Types of HDAC Inhibitors 3.5.3. Therapeutic Applications of HDAC Inhibitors 4. HDAC Inhibitors: Market Landscape 4.1. Chapter Overview 4.2. Development Pipeline of HDAC Inhibitors 4.3. Distribution by Phase of Development 4.4. Distribution by Therapeutic Area 4.5. Distribution by Class Specificity 4.6. Distribution by Type of Developer 4.7. Distribution by Geography 4.8. Active Industry Players 5. Drug Profiles: Marketed And Late-Stage HDAC Inhibitors 5.1. Chapter Overview 5.2. Company and Drug Profiles: Marketed and Phase III Molecules 5.2.1. Celgene Corporation 5.2.3. Novartis 5.2.4. Shenzhen Chipscreen Biosciences 5.2.5. Syndax Pharmaceuticals 5.3. Drug Profiles: Phase II Molecules 5.3.1. Abexinostat (PCI-24781) 5.3.2. CUDC-907 5.3.3. FRM-0334 (EVP-0334) 5.3.4. Givinostat (ITF2357) 5.3.5. Mocetinostat (MGCD103) 5.3.6. Pracinostat (SB939) 5.3.7. Resminostat (4SC-201) 5.3.8. SFX-01 5.3.9. SHAPE (SHP-141) 5.3.10. Tefinostat (CHR-2845) 6. Key Insights: Therapeutic Area, Class Specificity, Clinical Endpoints 6.1. Clinical Development Analysis: Class Specificity and Therapeutic Areas 6.2. Clinical Development Analysis: Developer Landscape 6.3. Clinical Development Analysis: Trial Endpoint Comparison 7. Market Forecast And Opportunity Analysis 7.1. Chapter Overview 7.2. Scope and Limitations 7.3. Forecast Methodology 7.4. Overall HDAC Inhibitors Market 7.5. HDAC Inhibitors Market: Individual Forecasts 7.5.1. Zolinza (Merck) 7.5.2. Istodax® (Celgene Corporation) 7.5.3. Beleodaq® (Onxeo) 7.5.4. Farydak® (Novartis) 7.5.5. Epidaza® (Shenzhen Chipscreen Biosciences) 7.5.6. Entinostat (Syndax Pharmaceuticals) 7.5.7. Abexinostat (Pharmacyclics) 7.5.8. CUDC-907 (Curis) 7.5.9. FRM-0334 (FORUM Pharmaceuticals) 7.5.10. Mocetinostat (Mirati Therapeutics) 7.5.11. Pracinostat (MEI Pharma) 7.5.12. Resminostat (4SC, Menarini, Yakult Honsha) 7.5.13. SFX-01 (Evgen Pharma) 7.5.14. SHP-141 (TetraLogic Pharmaceuticals) 7.5.15. Tefinostat (Chroma Therapeutics) 8. Publication Analysis 8.1. Chapter Overview 8.2. HDAC Inhibitors: Publications 8.3. Publication Analysis: Quarterly Distribution 8.4. Publication Analysis: Distribution by HDAC Inhibitor Class 8.5. Publication Analysis: Distribution by Drugs Studied 8.6. Publication Analysis: Distribution by Therapeutic Area 8.7. Publication Analysis: Distribution by Journals 8.8. Publication Analysis: Distribution by Phase of Development 8.9. Publication Analysis: Distribution by Type of Therapy 9. Social Media: Emerging Trends 9.1. Chapter Overview 9.1.1. Trends on Twitter 9.1.2. Trends on Facebook 10. Conclusion 10.1. The Pipeline is Healthy with Several Molecules in Preclinical Stages of Development 10.2. HDAC Inhibitors Cater to a Wide Spectrum of Disease Areas 10.3. Class Specific HDAC Inhibitors Have Been Explored for a More Targeted Approach 10.4. The Interest is Gradually Rising Amongst Both Industry and Non-Industry Players 10.5. Supported by a Robust Preclinical Pipeline, HDAC Inhibitors are Expected to Emerge as A Multi-Billion Dollar Market 11. Interview Transcripts 11.1. Chapter Overview 11.2. Dr. Simon Kerry, CEO, Karus Therapeutics 11.3. Dr. James Christensen, CSO and Senior VP, Mirati Therapeutics 11.4. Dr. Hyung J. Chun, MD, FAHA, Associate Professor of Medicine, Yale School of Medicine 12. Appendix 1: Tabulated Data 13. Appendix 2: List Of Companies And Organizations Companies Mentioned - 4SC - AACR - AbbVie - Acceleron Pharma - Acetylon Pharmaceuticals - Active Biotech - Agios Pharmaceuticals - ASH - Arno Therapeutics - Astellas Pharma - Bayer Schering Pharma - Baylor College of Medicine - BioMarin - Bionor Immuno - bluebird bio - Case Comprehensive Cancer Center - Celera Genomics - Celgene - Celleron Therapeutics - Centre de Recherche en Cancérologie - CETYA Therapeutics - CHDI Foundation - Chipscreen Biosciences - Chong Kun Dang Pharmaceutical - Chroma Therapeutics - Croix-Rousse Hospital - CrystalGenomics - Curis - DAC - Diaxonhit - DNA Therapeutics - Duke University - ECOG-ACRIN Cancer Research Group - Eddingpharm - Eisai - Epizyme - Errant Gene Therapeutics - European Calcified Tissue Society - Evgen Pharma - FORMA Therapeutics - FORUM Pharmaceuticals - Fudan University - Genentech - Genextra - Gilead - Gloucester Pharmaceuticals - GNT Biotech - GSK - Harvard Medical School - Henan Cancer Hospital - HUYA Biosciences - Ikerchem - Imperial College London - In2Gen - International Bone and Mineral Society - Israel Cancer Association and Bar Ilan University - Italfarmaco - Johnson and Johnson - Kalypsys - Karus Therapeutics - King's College, University of London - Kyoto Prefectural University of Medicine - Kyoto University - Kyowa Hakko Kirin - Leukemia and Lymphoma Society - Lymphoma Academic Research Organization - Massachusetts General Hospital - Mayo Clinic - MedImmune - MEI Pharma - Memorial Sloan-Kettering Cancer Center - Menarini - Merck - MethylGene - Mirati Therapeutics - Morphosys - Mundipharma-EDO - National Brain Research Centre - National Comprehensive Cancer Network - National Taiwan University - NCI - Novartis - NuPotential - Oceanyx Pharma - Oncolys Biopharma - Onxeo - Onyx - Orchid Pharma - Paterson Institute for Cancer Research - Pfizer - Pharmacyclics - Pharmion Corporation - Quimatryx - Quintiles - Repligen - Respiratorius - Roche - Rodin Therapeutics - Royal Veterinary College, University of London - Ruijin Hospital - S*Bio - Sarcoma Alliance for Research through Collaboration - Seattle Genetics - Servier Canada - Shape Pharmaceuticals - Sidney Kimmel Comprehensive Cancer Center - Sigma Tau Pharmaceuticals - Signal Rx - SpeBio - Spectrum Pharmaceuticals - Stanley Center for Psychiatric Research - Sutro Biopharma - Syndax Pharmaceuticals - Synovo GmbH - Taipei Medical University - TetraLogic Pharmaceuticals - University of Liverpool - University of Messina - University of Miami - Vanderbilt University School of Medicine - Ventana Medical Systems - Vilnius University - Yakult Honsha - Yale University - Yonsei University College of Medicine For more information about this report visit http://www.researchandmarkets.com/research/srvj3j/hdac_inhibitors


Thaler F.,Italian National Cancer Institute | Mercurio C.,Genextra
ChemMedChem | Year: 2014

Histone deacetylases (HDACs) are widely studied targets for the treatment of cancer and other diseases. Up to now, over twenty HDAC inhibitors have entered clinical studies and two of them have already reached the market, namely the hydroxamic acid derivative SAHA (vorinostat, Zolinza) and the cyclic depsipeptide FK228 (romidepsin, Istodax) that have been approved for the treatment of cutaneous T-cell lymphoma (CTCL). A common aspect of the first HDAC inhibitors is the absence of any particular selectivity towards specific isozymes. Some of molecules resulted to be "pan"-HDAC inhibitors, while others are classa I selective. In the meantime, the knowledge of HDAC biology has continuously progressed. Key advances in the structural biology of various isozymes, reliable molecular homology models as well as suitable biological assays have provided new tools for drug discovery activities. This Minireview aims at surveying these recent developments as well as the design, synthesis and biological characterization of isoform-selective derivatives. © 2014 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim.


Di Micco R.,FIRC Institute of Molecular Oncology Foundation | Di Micco R.,New York University | Sulli G.,FIRC Institute of Molecular Oncology Foundation | Dobreva M.,FIRC Institute of Molecular Oncology Foundation | And 14 more authors.
Nature Cell Biology | Year: 2011

Two major mechanisms have been causally implicated in the establishment of cellular senescence: the activation of the DNA damage response (DDR) pathway and the formation of senescence-associated heterochromatic foci (SAHF). Here we show that in human fibroblasts resistant to premature p16 INK4a induction, SAHF are preferentially formed following oncogene activation but are not detected during replicative cellular senescence or on exposure to a variety of senescence-inducing stimuli. Oncogene-induced SAHF formation depends on DNA replication and ATR (ataxia telangiectasia and Rad3-related). Inactivation of ATM (ataxia telangiectasia mutated) or p53 allows the proliferation of oncogene-expressing cells that retain increased heterochromatin induction. In human cancers, levels of heterochromatin markers are higher than in normal tissues, and are independent of the proliferative index or stage of the tumours. Pharmacological and genetic perturbation of heterochromatin in oncogene-expressing cells increase DDR signalling and lead to apoptosis. In vivo, a histone deacetylase inhibitor (HDACi) causes heterochromatin relaxation, increased DDR, apoptosis and tumour regression. These results indicate that heterochromatin induced by oncogenic stress restrains DDR and suggest that the use of chromatin-modifying drugs in cancer therapies may benefit from the study of chromatin and DDR status of tumours. © 2011 Macmillan Publishers Limited. All rights reserved.


Leiva M.,University Paris Diderot | Moretti S.,Italian National Cancer Institute | Soilihi H.,University Paris Diderot | Pallavicini I.,Italian National Cancer Institute | And 8 more authors.
Leukemia | Year: 2012

Aberrant histone acetylation was physiopathologically associated with the development of acute myeloid leukemias (AMLs). Reversal of histone deacetylation by histone deacetylase inhibitor (HDACis) activates a cell death program that allows tumor regression in mouse models of AMLs. We have used several models of PML-RARA-driven acute promyelocytic leukemias (APLs) to analyze the in vivo effects of valproic acid, a well-characterized HDACis. Valproic acid (VPA)-induced rapid tumor regression and sharply prolonged survival. However, discontinuation of treatment was associated to an immediate relapse. In vivo, as well as ex vivo, VPA-induced terminal granulocytic differentiation. Yet, despite full differentiation, leukemia-initiating cell (LIC) activity was actually enhanced by VPA treatment. In contrast to all-trans retinoic acid (ATRA) or arsenic, VPA did not degrade PML-RARA. However, in combination with ATRA, VPA synergized for PML-RARA degradation and LIC eradication in vivo. Our studies indicate that VPA triggers differentiation, but spares LIC activity, further uncouple differentiation from APL clearance and stress the importance of PML-RARA degradation in APL cure. © 2012 Macmillan Publishers Limited.


PubMed | Genextra, NiKem Research Srl, Italian National Cancer Institute and University of Milan
Type: | Journal: European journal of medicinal chemistry | Year: 2016

In the last decades, inhibitors of histone deacetylases (HDAC) have become an important class of anti-cancer agents. In a previous study we described the synthesis of spiro[chromane-2,4-piperidine]hydroxamic acid derivatives able to inhibit histone deacetylase enzymes. Herein, we present our exploration for new derivatives by replacing the piperidine moiety with various cycloamines. The goal was to obtain highly potent compounds with a good invitro ADME profile. In addition, molecular modeling studies unravelled the binding mode of these inhibitors.

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