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Susan Reijntjes, Muna Albayaty, James Bush, Joseph Cheriyan, Anthea Cromie, Annelize Koch, Michael Hammond, Stuart Mair, Peter Scholes, Ulrike Lorch, Steffan Stringer, Jorg Taubel, Timothy C Hardman
The Association for Human Pharmacology in the Pharmaceutical Industry (AHPPI) annual meeting focused on the changing face of early phase drug development and opened with a keynote speech concerning the revolution in pharmaceutical medicine over the last 30 years and the impact this has had on the way patients are treated. Examples were presented of how translational pharmaceutics is being used to tackle the high drug candidate failure rate and is improving productivity when moving drug candidates from the laboratory through to clinical proof of concept...
2018: Frontiers in Pharmacology
Yihua Wang, Shan Zhong, Christopher J Schofield, Peter J Ratcliffe, Xin Lu
Hypoxia plays a crucial role at cellular and physiological levels in all animals. The responses to chronic hypoxia are, at least substantially, orchestrated by activation of the hypoxia inducible transcription factors (HIFs), whose stability and subsequent transcriptional activation are regulated by HIF hydroxylases. Factor inhibiting HIF (FIH), initially isolated as a HIFα interacting protein following a yeast two-hybrid screen, is an asparaginyl hydroxylase that negatively regulates transcriptional activation by HIF...
November 19, 2018: Journal of Cell Science
Vanessa D Chaplin, John A Hangasky, Hsin-Ting Huang, Ran Duan, Michael J Maroney, Michael J Knapp
α-Ketoglutarate (αKG) dependent oxygenases comprise a large superfamily of enzymes that activate O2 for varied reactions. While most of these enzymes contain a nonheme Fe bound by a His2 (Asp/Glu) facial triad, a small number of αKG-dependent halogenases require only the two His ligands to bind Fe and activate O2 . The enzyme "factor inhibiting HIF" (FIH) contains a His2 Asp facial triad and selectively hydroxylates polypeptides; however, removal of the Asp ligand in the Asp201→Gly variant leads to a highly active enzyme, seemingly without a complete facial triad...
October 15, 2018: Inorganic Chemistry
Jengmin Kang, Yang-Sook Chun, June Huh, Jong-Wan Park
The N-terminal acetyltransferase A (NatA) complex, which is composed of NAA10 and NAA15, catalyzes N-terminal acetylation of many proteins in a co-translational manner. Structurally, the catalytic subunit NAA10 was believed to have no activity toward an internal lysine residue because the gate of its catalytic pocket is too narrow. However, several studies have demonstrated that the monomeric NAA10 can acetylate the internal lysine residues of several substrates including hypoxia-inducible factor 1α (HIF-1α)...
October 2018: Redox Biology
Shyam R Iyer, Vanessa D Chaplin, Michael J Knapp, Edward I Solomon
FIH [factor inhibiting HIF (hypoxia inducible factor)] is an α-ketoglutarate (αKG)-dependent nonheme iron enzyme that catalyzes the hydroxylation of the C-terminal transactivation domain (CAD) asparagine residue in HIF-1α to regulate cellular oxygen levels. The role of the facial triad carboxylate ligand in O2 activation and catalysis was evaluated by replacing the Asp201 residue with Gly (D201G), Ala (D201A), and Glu (D201E). Magnetic circular dichroism (MCD) spectroscopy showed that the (FeII )FIH variants were all 6-coordinate (6C) and the αKG plus CAD bound FIH variants were all 5-coordinate (5C), mirroring the behavior of the wild-type ( wt) enzyme...
September 19, 2018: Journal of the American Chemical Society
Xiaolian Cai, Dawei Zhang, Jing Wang, Xing Liu, Gang Ouyang, Wuhan Xiao
Many aerobic organisms have developed molecular mechanism to tolerate hypoxia, but the specifics of these mechanisms remain poorly understood. It is important to develop genetic methods that confer increased hypoxia tolerance to intensively farmed aquatic species, as these are maintained in environments with limited available oxygen. As an asparaginyl hydroxylase of hypoxia-inducible factors (HIFs), factor inhibiting HIF (FIH) inhibits transcriptional activation of hypoxia-inducible genes by blocking the association of HIFs with the transcriptional coactivators CREB-binding protein (CBP) and p300...
October 5, 2018: Journal of Biological Chemistry
Jie Shen, Brandon Swift, Richard Mamelok, Samuel Pine, John Sinclair, Mayssa Attar
A milestone step in translational science to transform basic scientific discoveries into therapeutic applications is the advancement of a drug candidate from preclinical studies to initial human testing. First-in-human (FIH) trials serve as the link to advance new promising drug candidates and are conducted primarily to determine the safe dose range for further clinical development. Cross-functional collaboration is essential to ensure efficient and successful FIH trials. The aim of this publication is to serve as a tutorial for conducting FIH trials for both small molecule and biological drug candidates with topics covering regulatory requirements, preclinical safety testing, study design considerations, safety monitoring, biomarker assessment, and global considerations...
July 26, 2018: Clinical and Translational Science
Frank R Brennan, Laura Andrews, Antonio R Arulanandam, Jorg Blumel, Jim Fikes, Christine Grimaldi, Janice Lansita, Lise I Loberg, Tim MacLachlan, Mark Milton, Suezanne Parker, Jay Tibbitts, Jayanthi Wolf, Krishna P Allamneni
Nonclinical safety testing of biopharmaceuticals can present significant challenges to human risk assessment with these innovative and often complex drugs. Emerging topics in this field were discussed recently at the 2016 Annual US BioSafe General Membership meeting. The presentations and subsequent discussions from the main sessions are summarized. The topics covered included: (i) specialty biologics (oncolytic virus, gene therapy, and gene editing-based technologies), (ii) the value of non-human primates (NHPs) for safety assessment, (iii) challenges in the safety assessment of immuno-oncology drugs (T cell-dependent bispecifics, checkpoint inhibitors, and costimulatory agonists), (iv) emerging therapeutic approaches and modalities focused on microbiome, oligonucleotide, messenger ribonucleic acid (mRNA) therapeutics, (v) first in human (FIH) dose selection and the minimum anticipated biological effect level (MABEL), (vi) an update on current regulatory guidelines, International Council for Harmonization (ICH) S1, S3a, S5, S9 and S11 and (vii) breakout sessions that focused on bioanalytical and PK/PD challenges with bispecific antibodies, cytokine release in nonclinical studies, determining adversity and NOAEL for biologics, the value of second species for toxicology assessment and what to do if there is no relevant toxicology species...
July 17, 2018: Regulatory Toxicology and Pharmacology: RTP
Biying Zhu, Xiuye Cao, Wenqiang Zhang, Guoping Pan, Qing Yi, Wenbin Zhong, Daoguang Yan
The enhanced expression of miR-31 has been observed in many human malignancies including lung cancer, and this microRNA regulates several aspects of oncogenesis. However, the role of miR-31-5p in energy metabolism remains elusive. Here, we confirm that H1299 and A549 cells, 2 lung cancer cell lines, relay on aerobic glycolysis as main source of ATP. Inhibition of miR-31-5p leads to decreased glycolysis and ATP production, while miR-31-5p overexpression increases them. Hypoxia inducible factor 1 (HIF-1) up-regulates the expression of glycolytic enzymes, and the HIF-1α inhibitor (FIH) inhibits HIF-1 activity...
July 13, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
(no author information available yet)
No abstract text is available yet for this article.
July 1, 2018: Cancer Research
Priyanshu Bhargava, Anjani Kumari, Jayarani F Putri, Yoshiyuki Ishida, Keiji Terao, Sunil C Kaul, Durai Sundar, Renu Wadhwa
Honeybee propolis and its bioactive component, caffeic acid phenethyl ester (CAPE), are known for a variety of therapeutic potentials. By recruiting a cell-based reporter assay for screening of hypoxia-modulating natural drugs, we identified CAPE as a pro-hypoxia factor. In silico studies were used to probe the capacity of CAPE to interact with potential hypoxia-responsive proteins. CAPE could not dock into hypoxia inducing factor (HIF-1), the master regulator of hypoxia response pathway. On the other hand, it was predicted to bind to factor inhibiting HIF (FIH-1)...
September 2018: Cell Stress & Chaperones
Xuemei Liu, Pei Hu, Yongsheng Wang, Xizhu Wang, Jinghua Huang, Jin Li, Cheng Li, Hongyun Wang, Ji Jiang
Monocyte locomotion inhibitory factor (MLIF, Met-Gln-Cys-Asn-Ser), a pentapeptide with anti-inflammatory activity, was developed for neural protection in acute ischemic stroke. Determination of MLIF in human plasma samples is of great importance for pharmacokinetic evaluation in clinical studies. A reliable and sensitive method based on ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) was established for the measurement of MLIF in human plasma. Instability of peptide in matrix was the primary challenge in method development, which was properly resolved by addition of acidification reagents like sulfuric acid...
August 5, 2018: Journal of Pharmaceutical and Biomedical Analysis
Shi Deng, Bo Yang, Zheng-Ju Ren, Qiang Dong
OBJECTIVE: To detect the expression and growth regulation effects of the factor inhibiting hypoxia-inducible factor (FIH-1) in renal carcinoma cells. METHODS: The expressions of FIH-1,hypoxia inducible factor (HIF) and vascular endothelial growth factor (VEGF) were examined in OS-RC-2 and 786-0 cell lines via real-time PCR (RT-PCR) and Western blot. Overexpression plasmid of FIH-1 were designed and constructed as EX-V1104-M45- FIH-1. After the transfection of the plasmid into OS-RC-2 and 786-0 cells,the expression levels of FIH-1,HIF and VEGF were measured by RT-PCR and Western blot,while cell proliferation was tested by MTT...
January 2018: Sichuan da Xue Xue Bao. Yi Xue Ban, Journal of Sichuan University. Medical Science Edition
Jennifer L Wylie, Aileen House, Peter J Mauser, Shari Sellers, Jenna Terebetski, Zhenyu Wang, Jason D Ehrick
The factors that influence inhaled first-in-human (FIH) device and formulation selection often differ significantly from the factors that have influenced the preceding preclinical experiments and inhalation toxicology work. In order to minimize the risk of delivery issues negatively impacting a respiratory pipeline program, the preclinical and FIH delivery systems must be considered holistically. This topic will be covered in more detail in this paper. Several examples will be presented that highlight how appropriate scientific strategy can help bridge the gap between delivering to preclinical species and human...
May 2018: Therapeutic Delivery
Jingwei Sim, Andrew S Cowburn, Asis Palazon, Basetti Madhu, Petros A Tyrakis, David Macías, David M Bargiela, Sandra Pietsch, Michael Gralla, Colin E Evans, Thaksaon Kittipassorn, Yu C J Chey, Cristina M Branco, Helene Rundqvist, Daniel J Peet, Randall S Johnson
Animals require an immediate response to oxygen availability to allow rapid shifts between oxidative and glycolytic metabolism. These metabolic shifts are highly regulated by the HIF transcription factor. The factor inhibiting HIF (FIH) is an asparaginyl hydroxylase that controls HIF transcriptional activity in an oxygen-dependent manner. We show here that FIH loss increases oxidative metabolism, while also increasing glycolytic capacity, and that this gives rise to an increase in oxygen consumption. We further show that the loss of FIH acts to accelerate the cellular metabolic response to hypoxia...
April 3, 2018: Cell Metabolism
Peng Jin, Jengmin Kang, Myung Kyu Lee, Jong-Wan Park
Hypoxia-inducible factor 1 (HIF-1) is a key player in cellular response to hypoxia. The stability and transcriptional activity of this protein are oxygen-dependently regulated by the prolyl hydroxylases PHD1-3 and the asparaginyl hydroxylase FIH. Recently, ferritin heavy chain (FTH1) has been characterized to reinforce the HIF-1 signaling pathway in an indirect way through the inhibition of PHD activity by depleting the free iron pool in the cytoplasm. In the present study, we addressed the role of FTH1 in the FIH control of HIF-1 activity...
May 15, 2018: Biochemical and Biophysical Research Communications
Charles K Davis, Sreekala S Nampoothiri, G K Rajanikant
The constant failure of single-target drug therapies for ischemic stroke necessitates the development of novel pleiotropic pharmacological treatment approaches, to effectively combat the aftermath of this devastating disorder. The major objective of our study involves a multi-target drug repurposing strategy to stabilize hypoxia-inducible factor-1 α (HIF-1α) via a structure-based screening approach to simultaneously inhibit its regulatory proteins, PHD2, FIH, and pVHL. Out of 1424 Food and Drug Administration (FDA)-approved drugs that were screened, folic acid (FA) emerged as the top hit and its binding potential to PHD2, FIH, and pVHL was further verified by re-docking, molecular dynamics (MD) simulation and by Drug Affinity Responsive Target Stability (DARTS) assay...
November 2018: Molecular Neurobiology
Hans Ericsson, Karin Nelander, Maria Lagerstrom-Fermer, Clare Balendran, Maria Bhat, Ligia Chialda, Li-Ming Gan, Maria Heijer, Magnus Kjaer, John Lambert, Eva-Lotte Lindstedt, Gun-Britt Forsberg, Carl Whatling, Stanko Skrtic
We evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of AZD5718, a novel 5-lipooxygenase activating protein (FLAP) inhibitor, in a randomized, single-blind, placebo-controlled, first-in-human (FIH) study consisting of single and multiple ascending dosing (SAD and MAD) for 10 days in healthy subjects. Target engagement was measured by ex vivo calcium ionophore stimulated leukotriene B (LTB4 ) production in whole blood and endogenous leukotriene E (LTE4 ) in urine. No clinically relevant safety and tolerability findings were observed...
May 2018: Clinical and Translational Science
Clemens Muehlan, Jules Heuberger, Pierre-Eric Juif, Marie Croft, Joop van Gerven, Jasper Dingemanse
The orexin system regulates sleep and arousal and is targeted by ACT-541468, a new dual orexin receptor antagonist (DORA). Healthy male subjects received a single oral dose of 5-200 mg to assess safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), mass balance, metabolism, and absolute bioavailability utilizing a 14 C-labeled, orally and intravenously (i.v.) administered microtracer. The drug was safe and well tolerated; the PK profile was characterized by quick absorption and elimination, with median time to reach maximum concentration (tmax ) of 0...
November 2018: Clinical Pharmacology and Therapeutics
Kilian B Kennel, Julius Burmeister, Martin Schneider, Cormac T Taylor
The hypoxia-inducible factor (HIF) co-ordinates the adaptive transcriptional response to hypoxia in metazoan cells. The hypoxic sensitivity of HIF is conferred by a family of oxygen-sensing enzymes termed HIF hydroxylases. This family consists of three prolyl hydroxylases (PHD1-3) and a single asparagine hydroxylase termed factor inhibiting HIF (FIH). It has recently become clear that HIF hydroxylases are functionally non-redundant and have discrete but overlapping physiological roles. Furthermore, altered abundance or activity of these enzymes is associated with a number of pathologies...
September 2018: Journal of Physiology
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