Publications by authors named "Tzu-Lan Yeh"

12 Publications

  • Page 1 of 1

Structure-Activity Relationship and Crystallographic Studies on 4-Hydroxypyrimidine HIF Prolyl Hydroxylase Domain Inhibitors.

ChemMedChem 2020 02 3;15(3):270-273. Epub 2019 Dec 3.

Department of Chemistry, University of Oxford Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK.

The 2-oxoglutarate-dependent hypoxia inducible factor prolyl hydroxylases (PHDs) are targets for treatment of a variety of diseases including anaemia. One PHD inhibitor is approved for use for the treatment of renal anaemia and others are in late stage clinical trials. The number of reported templates for PHD inhibition is limited. We report structure-activity relationship and crystallographic studies on a promising class of 4-hydroxypyrimidine-containing PHD inhibitors.
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http://dx.doi.org/10.1002/cmdc.201900557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496690PMC
February 2020

The Clinically Used Iron Chelator Deferasirox Is an Inhibitor of Epigenetic JumonjiC Domain-Containing Histone Demethylases.

ACS Chem Biol 2019 08 19;14(8):1737-1750. Epub 2019 Jul 19.

Institute of Pharmaceutical Sciences , Albert-Ludwigs-Universität Freiburg , Albertstraße 25 , 79104 Freiburg i.Br. , Germany.

Fe(II)- and 2-oxoglutarate (2OG)-dependent JumonjiC domain-containing histone demethylases (JmjC KDMs) are "epigenetic eraser" enzymes involved in the regulation of gene expression and are emerging drug targets in oncology. We screened a set of clinically used iron chelators and report that they potently inhibit JMJD2A (KDM4A) . Mode of action investigations revealed that one compound, deferasirox, is a active site-binding inhibitor as shown by kinetic and spectroscopic studies. Synthesis of derivatives with improved cell permeability resulted in significant upregulation of histone trimethylation and potent cancer cell growth inhibition. Deferasirox was also found to inhibit human 2OG-dependent hypoxia inducible factor prolyl hydroxylase activity. Therapeutic effects of clinically used deferasirox may thus involve transcriptional regulation through 2OG oxygenase inhibition. Deferasirox might provide a useful starting point for the development of novel anticancer drugs targeting 2OG oxygenases and a valuable tool compound for investigations of KDM function.
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http://dx.doi.org/10.1021/acschembio.9b00289DOI Listing
August 2019

Small-molecules that covalently react with a human prolyl hydroxylase - towards activity modulation and substrate capture.

Chem Commun (Camb) 2019 Jan;55(8):1020-1023

Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.

We describe covalently binding modulators of the activity of human prolyl hydroxylase domain 2 (PHD2) and studies towards a strategy for photocapture of PHD2 substrates. Reversible active site binding of electrophile bearing compounds enables susbsequent covalent reaction with a lysine residue (K408) in the flexible C-terminal region of PHD2 to give a modified protein that retains catalytic activity.
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http://dx.doi.org/10.1039/c8cc07706aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350621PMC
January 2019

Selective Inhibitors of a Human Prolyl Hydroxylase (OGFOD1) Involved in Ribosomal Decoding.

Chemistry 2019 Feb 8;25(8):2019-2024. Epub 2019 Jan 8.

Department of Chemistry, University of Oxford, Oxford, OX1 3TA, UK.

Human prolyl hydroxylases are involved in the modification of transcription factors, procollagen, and ribosomal proteins, and are current medicinal chemistry targets. To date, there are few reports on inhibitors selective for the different types of prolyl hydroxylases. We report a structurally informed template-based strategy for the development of inhibitors selective for the human ribosomal prolyl hydroxylase OGFOD1. These inhibitors did not target the other human oxygenases tested, including the structurally similar hypoxia-inducible transcription factor prolyl hydroxylase, PHD2.
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http://dx.doi.org/10.1002/chem.201804790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471485PMC
February 2019

A Fluorescent Benzo[g]isoquinoline-Based HIF Prolyl Hydroxylase Inhibitor for Cellular Imaging.

ChemMedChem 2019 01 21;14(1):94-99. Epub 2018 Dec 21.

Department of Chemistry and Pharmacy, Inorganic and Organometallic Chemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Egerlandstraße 1, 91058, Erlangen, Germany.

Prolyl hydroxylation domain (PHD) enzymes catalyze the hydroxylation of the transcription factor hypoxia-inducible factor (HIF) and serve as cellular oxygen sensors. HIF and the PHD enzymes regulate numerous potentially tissue-protective target genes which can adapt cells to metabolic and ischemic stress. We describe a fluorescent PHD inhibitor (1-chloro-4-hydroxybenzo[g]isoquinoline-3-carbonyl)glycine which is suited to fluorescence-based detection assays and for monitoring PHD inhibitors in biological systems. In cell-based assays, application of the fluorescent PHD inhibitor allowed co-localization with a cellular PHD enzyme and led to live cell imaging of processes involved in cellular oxygen sensing.
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http://dx.doi.org/10.1002/cmdc.201800483DOI Listing
January 2019

Molecular and cellular mechanisms of HIF prolyl hydroxylase inhibitors in clinical trials.

Chem Sci 2017 Nov 11;8(11):7651-7668. Epub 2017 Sep 11.

Chemistry Research Laboratory , Department of Chemistry , University of Oxford , Oxford OX1 3TA , UK . Email:

Inhibition of the human 2-oxoglutarate (2OG) dependent hypoxia inducible factor (HIF) prolyl hydroxylases (human PHD1-3) causes upregulation of HIF, thus promoting erythropoiesis and is therefore of therapeutic interest. We describe cellular, biophysical, and biochemical studies comparing four PHD inhibitors currently in clinical trials for anaemia treatment, that describe their mechanisms of action, potency against isolated enzymes and in cells, and selectivities representatives of other human 2OG oxygenase subfamilies. The 'clinical' PHD inhibitors are potent inhibitors of PHD catalyzed hydroxylation of the HIF-α oxygen dependent degradation domains (ODDs), and selective against most, but not all, representatives of other human 2OG dependent dioxygenase subfamilies. Crystallographic and NMR studies provide insights into the different active site binding modes of the inhibitors. Cell-based results reveal the inhibitors have similar effects on the upregulation of HIF target genes, but differ in the kinetics of their effects and in extent of inhibition of hydroxylation of the N- and C-terminal ODDs; the latter differences correlate with the biophysical observations.
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http://dx.doi.org/10.1039/c7sc02103hDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5802278PMC
November 2017

Normal tissue radioprotection by amifostine via Warburg-type effects.

Sci Rep 2016 08 10;6:30986. Epub 2016 Aug 10.

Cancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

The mechanism of Amifostine (WR-2721) mediated radioprotection is poorly understood. The effects of amifostine on human basal metabolism, mouse liver metabolism and on normal and tumor hepatic cells were studied. Indirect calorimetric canopy tests showed significant reductions in oxygen consumption and of carbon dioxide emission in cancer patients receiving amifostine. Glucose levels significantly decreased and lactate levels increased in patient venous blood. Although amifostine in vitro did not inhibit the activity of the prolyl-hydroxylase PHD2, experiments with mouse liver showed that on a short timescale WR-1065 induced expression of the Hypoxia Inducible Factor HIF1α, lactate dehydrogenase LDH5, glucose transporter GLUT2, phosphorylated pyruvate dehydrogenase pPDH and PDH-kinase. This effect was confirmed on normal mouse NCTC hepatocytes, but not on hepatoma cells. A sharp reduction of acetyl-CoA and ATP levels in NCTC cells indicated reduced mitochondrial usage of pyruvate. Transient changes of mitochondrial membrane potential and reactive oxygen species ROS production were evident. Amifostine selectively protects NCTC cells against radiation, whilst HepG2 neoplastic cells are sensitized. The radiation protection was correlates with HIF levels. These findings shed new light on the mechanism of amifostine cytoprotection and encourage clinical research with this agent for the treatment of primary and metastatic liver cancer.
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http://dx.doi.org/10.1038/srep30986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4978965PMC
August 2016

Therapeutic targeting of oxygen-sensing prolyl hydroxylases abrogates ATF4-dependent neuronal death and improves outcomes after brain hemorrhage in several rodent models.

Sci Transl Med 2016 Mar;8(328):328ra29

Sperling Center for Hemorrhagic Stroke Recovery, Burke Medical Research Institute, White Plains, NY 10605, USA. Feil Family Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, NY 10065, USA.

Disability or death due to intracerebral hemorrhage (ICH) is attributed to blood lysis, liberation of iron, and consequent oxidative stress. Iron chelators bind to free iron and prevent neuronal death induced by oxidative stress and disability due to ICH, but the mechanisms for this effect remain unclear. We show that the hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) family of iron-dependent, oxygen-sensing enzymes are effectors of iron chelation. Molecular reduction of the three HIF-PHD enzyme isoforms in the mouse striatum improved functional recovery after ICH. A low-molecular-weight hydroxyquinoline inhibitor of the HIF-PHD enzymes, adaptaquin, reduced neuronal death and behavioral deficits after ICH in several rodent models without affecting total iron or zinc distribution in the brain. Unexpectedly, protection from oxidative death in vitro or from ICH in vivo by adaptaquin was associated with suppression of activity of the prodeath factor ATF4 rather than activation of an HIF-dependent prosurvival pathway. Together, these findings demonstrate that brain-specific inactivation of the HIF-PHD metalloenzymes with the blood-brain barrier-permeable inhibitor adaptaquin can improve functional outcomes after ICH in several rodent models.
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http://dx.doi.org/10.1126/scitranslmed.aac6008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341138PMC
March 2016

A cell-permeable ester derivative of the JmjC histone demethylase inhibitor IOX1.

ChemMedChem 2014 Mar 6;9(3):566-71. Epub 2014 Feb 6.

Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA (UK).

The 2-oxoglutarate (2OG)-dependent Jumonji C domain (JmjC) family is the largest family of histone lysine demethylases. There is interest in developing small-molecule probes that modulate JmjC activity to investigate their biological roles. 5-Carboxy-8-hydroxyquinoline (IOX1) is the most potent broad-spectrum inhibitor of 2OG oxygenases, including the JmjC demethylases, reported to date; however, it suffers from low cell permeability. Here, we describe structure-activity relationship studies leading to the discovery of an n-octyl ester form of IOX1 with improved cellular potency (EC50 value of 100 to 4 μM). These findings are supported by in vitro inhibition and selectivity studies, docking studies, activity versus toxicity analysis in cell cultures, and intracellular uptake measurements. The n-octyl ester was found to have improved cell permeability; it was found to inhibit some JmjC demethylases in its intact ester form and to be more selective than IOX1. The n-octyl ester of IOX1 should find utility as a starting point for the development of JmjC inhibitors and as a use as a cell-permeable tool compound for studies investigating the roles of 2OG oxygenases in epigenetic regulation.
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http://dx.doi.org/10.1002/cmdc.201300428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503230PMC
March 2014

Regulation of the Sre1 hypoxic transcription factor by oxygen-dependent control of DNA binding.

Mol Cell 2011 Oct;44(2):225-34

Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Regulation of gene expression plays an integral role in adaptation of cells to hypoxic stress. In mammals, prolyl hydroxylases control levels of the central transcription factor hypoxia inducible factor (HIF) through regulation of HIFα subunit stability. Here, we report that the hydroxylase Ofd1 regulates the Sre1 hypoxic transcription factor in fission yeast by controlling DNA binding. Prolyl hydroxylases require oxygen as a substrate, and the activity of Ofd1 regulates Sre1-dependent transcription. In the presence of oxygen, Ofd1 binds the Sre1 N-terminal transcription factor domain (Sre1N) and inhibits Sre1-dependent transcription by blocking DNA binding. In the absence of oxygen, the inhibitor Nro1 binds Ofd1, thereby releasing Sre1N and leading to activation of genes required for hypoxic growth. In contrast to the HIF system, where proline hydroxylation is essential for regulation, Ofd1 inhibition of Sre1N does not require hydroxylation and, thus, defines a new mechanism for hypoxic gene regulation.
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http://dx.doi.org/10.1016/j.molcel.2011.08.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3208185PMC
October 2011

The hypoxic regulator of sterol synthesis nro1 is a nuclear import adaptor.

Structure 2011 Apr;19(4):503-14

Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, 725 N Wolfe Street, Baltimore, MD 21205, USA.

Fission yeast protein Sre1, the homolog of the mammalian sterol regulatory element-binding protein (SREBP), is a hypoxic transcription factor required for sterol homeostasis and low-oxygen growth. Nro1 regulates the stability of the N-terminal transcription factor domain of Sre1 (Sre1N) by inhibiting the action of the prolyl 4-hydroxylase-like Ofd1 in an oxygen-dependent manner. The crystal structure of Nro1 determined at 2.2 Å resolution shows an all-α-helical fold that can be divided into two domains: a small N-terminal domain, and a larger C-terminal HEAT-repeat domain. Follow-up studies showed that Nro1 defines a new class of nuclear import adaptor that functions both in Ofd1 nuclear localization and in the oxygen-dependent inhibition of Ofd1 to control the hypoxic response.
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http://dx.doi.org/10.1016/j.str.2011.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086001PMC
April 2011

A compact beta model of huntingtin toxicity.

J Biol Chem 2011 Mar 5;286(10):8188-8196. Epub 2011 Jan 5.

From the Division of Neurobiology, Department of Psychiatry, Children's Medical Surgical Center,. Electronic address:

Huntington disease results from an expanded polyglutamine region in the N terminus of the huntingtin protein. HD pathology is characterized by neuronal degeneration and protein inclusions containing N-terminal fragments of mutant huntingtin. Structural information is minimal, though it is believed that mutant huntingtin polyglutamine adopts β structure upon conversion to a toxic form. To this end, we designed mammalian cell expression constructs encoding compact β variants of Htt exon 1 N-terminal fragment and tested their ability to aggregate and induce toxicity in cultured neuronal cells. In parallel, we performed molecular dynamics simulations, which indicate that constructs with expanded polyglutamine β-strands are stabilized by main-chain hydrogen bonding. Finally, we found a correlation between the reactivity to 3B5H10, an expanded polyglutamine antibody that recognizes a compact β rich hairpin structure, and the ability to induce cell toxicity. These data are consistent with an important role for a compact β structure in mutant huntingtin-induced cell toxicity.
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http://dx.doi.org/10.1074/jbc.M110.192013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3048705PMC
March 2011