AG490 promotes HIF-1α accumulation by inhibiting its hydroxylation.

Abstract:

:AG490 is a tyrphostin originally described as a Janus Activated Kinase (JAK) 2 inhibitor. AG490 also inhibits epidermal growth factor receptor (EGFR) and guanylyl cyclases (GC). More recently, AG490 was associated with oxidative stress protection in experimental acute kidney injury models. We now show that AG490 is also a strong activator of the Hypoxia Inducible Factor (HIF)-1. Under normoxic conditions HIF-1α is degraded through hydroxylation, von Hippel Lindau protein (VHL)-mediated ubiquitin tagging and proteasomal degradation. AG490 increased HIF-1α protein, but not HIF-1α mRNA levels, dose- and time-dependently in cultured endothelial, vascular smooth muscle and kidney proximal tubular epithelial cells. AG490 increased HIF-1α protein half-life, suggesting that HIF-1α protein accumulation resulted from a decreased degradation. In this regard, AG490 prevented HIF-1α hydroxylation and increased HIF-1α protein levels in human renal carcinoma cells expressing VHL, but did not further increase HIF-1α in VHL negative cells. AG490 did not prevent the proteasomal degradation of other proteins. HIF-1α was not upregulated by dominant negative JAK2constructs, tyrphostin AG9, the EGFR inhibitors erbstatin and genistein, the GC inhibitor Ly83583 or cGMP analogues. Finally, AG490 also increased HIF-1α transcriptional activity evidenced by the increased HIF-1α-dependent VEGF expression. In conclusion, AG490 is a novel HIF-1α activator that increases HIF-1α half-life and protein levels through interference with HIF-1α hydroxylation and VHL-mediated degradation. This action may contribute to the cell and tissue protective effects of AG490.

journal_name

Curr Med Chem

authors

Fernández-Sánchez R,Berzal S,Sánchez-Niño MD,Neria F,Gonçalves S,Calabia O,Tejedor A,Calzada MJ,Caramelo C,Deudero JJ,Ortiz A

doi

10.2174/092986712802002554

subject

Has Abstract

pub_date

2012-01-01 00:00:00

pages

4014-23

issue

23

eissn

0929-8673

issn

1875-533X

pii

CMC-EPUB-20120618-2

journal_volume

19

pub_type

杂志文章
  • Structure and ligand based drug design strategies in the development of novel 5- LOX inhibitors.

    abstract::Lipoxygenases (LOXs) are non-heme iron containing dioxygenases involved in the oxygenation of polyunsaturated fatty acids (PUFAs) such as arachidonic acid (AA). Depending on the position of insertion of oxygen, LOXs are classified into 5-, 8-, 9-, 12- and 15-LOX. Among these, 5-LOX is the most predominant isoform asso...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986712801661112

    authors: Aparoy P,Reddy KK,Reddanna P

    更新日期:2012-01-01 00:00:00

  • Dual-targeting approach on histamine H3 and sigma-1 receptor ligands as promising pharmacological tools in the treatment of CNS-linked disorders.

    abstract::With the recent market approval of Pitolisant (Wakix®), the interest in clinical application for novel multifunctional histamine H3 receptor antagonists has clearly increased. Several combinations of different H3R pharmacophores with pharmacophoric elements of other G-protein coupled receptors, transporters or enzymes...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章

    doi:10.2174/0929867327666200806103144

    authors: Szczepańska K,Kuder KJ,Kieć-Kononowicz K

    更新日期:2020-08-05 00:00:00

  • Managing the liabilities arising from structural alerts: a safe philosophy for medicinal chemists.

    abstract::Bioactivation of xenobiotics can, in certain circumstances, result in the formation of reactive electrophilic species. These reactive metabolites may covalently modify proteins and macromolecules and it has been suggested that protein modification is a key initial step in provoking idiosyncratic adverse drug reactions...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986711796391714

    authors: Edwards PJ,Sturino C

    更新日期:2011-01-01 00:00:00

  • Identification of enzyme inhibitors using combinatorial libraries.

    abstract::Potent enzyme inhibitors have long been recognized as powerful tools for assessing the physiological roles of enzymes and have led to the therapeutic drugs able to modulate their activities in vivo. However, to be valuable tools such inhibitors should be selective so that they do not interfere with other members of th...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867023371120

    authors: Batra S,Srinivasan T,Rastogi SK,Kundu B

    更新日期:2002-02-01 00:00:00

  • Cinnamic acid derivatives as anticancer agents-a review.

    abstract::Cinnamic acid and its phenolic analogues are natural substances. Chemically, in cinnamic acids the 3-phenyl acrylic acid functionality offers three main reactive sites; substitution at the phenyl ring, addition at the α,β- unsaturation and the reactions of the carboxylic acid functionality. Owing to these chemical asp...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986711795471347

    authors: De P,Baltas M,Bedos-Belval F

    更新日期:2011-01-01 00:00:00

  • Multi-aspect candidates for repositioning: data fusion methods using heterogeneous information sources.

    abstract::Drug repositioning, an innovative therapeutic application of an old drug, has received much attention as a particularly costeffective strategy in drug R&D Recent work has indicated that repositioning can be promoted by utilizing a wide range of information sources, including medicinal chemical, target, mechanism, main...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章

    doi:

    authors: Arany Á,Bolgár B,Balogh B,Antal P,Mátyus P

    更新日期:2013-01-01 00:00:00

  • Can breast cancer stem cells evade the immune system?

    abstract::The evidence seems to be growing in favor of the stem cell theory of cancer with the emergence of studies demonstrating the parallel mechanisms of self renewing pathways in stem cells and particular subsets of cancer cells. The finding of leukemia stem cells and subsequently breast cancer stem cells (BCSC) further sup...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986712804485863

    authors: Nahas GR,Patel SA,Bliss SA,Rameshwar P

    更新日期:2012-01-01 00:00:00

  • The anti inflammatory effects of high density lipoproteins.

    abstract::It is well recognised that increased levels of high density lipoprotein (HDL) protect against atherosclerosis and correlate with improved prognosis for vascular disease associated events. While many of the atheroprotective effects of HDL are ascribed to the ability to remove cholesterol from the vasculature through th...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986709787458425

    authors: Murphy AJ,Chin-Dusting JP,Sviridov D,Woollard KJ

    更新日期:2009-01-01 00:00:00

  • Photobiostimulation on wound healing treatment by ClAlPc-nanoemulsion from a multiple-wavelength portable light source on a 3D-human stem cell dermal equivalent.

    abstract::This research evaluated the effect of multiple-wave lasertherapy on the healing process of surgical wounds based on in vitro models denominated stem-dermal equivalents. These human skin models were obtained from a co-culture of dermal cells and bone marrow mesenchymal stem cells. The experimental tests were carried ou...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章

    doi:10.2174/092986712803530502

    authors: Primo FL,de Paula LB,de Siqueira-Moura MP,Tedesco AC

    更新日期:2012-01-01 00:00:00

  • The synthesis and antiviral properties of acyclic nucleoside analogues with a phosphonomethoxy fragment in the side chain.

    abstract::Acyclic nucleoside analogues bearing phosphonomethoxy residues in the side chain (ANP) attract much attention due to a very beneficial combination of biological properties. Intensive work of organic chemists during the last two decades resulted in a large panel of new compounds that were evaluated as potential antivir...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986706778521896

    authors: Khandazhinskaya A,Yasko M,Shirokova E

    更新日期:2006-01-01 00:00:00

  • Therapeutic Macromolecular Iron Chelators.

    abstract::Iron is a key element for every single living process. On a fundamental level, targeting iron is a valuable approach for the treatment of disorders caused by iron overload. Utilizing iron chelators as therapeutic agents has received expanding consideration in chelation therapy. Approved low molecular weight (MW) iron ...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章

    doi:10.2174/0929867325666180904104318

    authors: Bulbake U,Singh A,Domb AJ,Khan W

    更新日期:2019-01-01 00:00:00

  • Functional, genetic and biochemical biomarkers of peripheral arterial disease.

    abstract::Patients with peripheral arterial disease (PAD) suffer from increased cardiovascular morbidity and mortality. The ankle brachial index has been widely used as an easy tool to identify and stratify patients with PAD, however its predictive value remains limited. Higher levels of inflammatory and prothrombotic biomarker...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986712800492959

    authors: Charakida M,Masi S,Tousoulis D

    更新日期:2012-01-01 00:00:00

  • Role of Vitamin D in Vascular Complications and Vascular Access Outcome in Patients with Chronic Kidney Disease.

    abstract::Vitamin D has been known for a long time as a major factor involved in the calcium- phosphate balance and homeostasis, along with parathyroid hormone (PTH). While vitamin D effects on calcium and phosphate are fully known, recent studies attempted to link vitamin D status and cardiovascular diseases. The involvement o...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867323666160405112019

    authors: Santoro D,Pellicanò V,Cernaro V,Lacava V,Lacquaniti A,Atteritano M,Buemi M

    更新日期:2016-01-01 00:00:00

  • New strategy in gene transfection by cationic transfection lipids with a cationic cholesterol.

    abstract::The present article reviews interesting cationic liposomes (cationic transfection lipids) with novel cationic cholesterol derivatives, a new strategy in gene transfection developed by our group and the presently accepted molecular mechanism of gene transfection. Use of confocal laser scanning microscopy and atomic for...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867033457395

    authors: Nakanishi M

    更新日期:2003-07-01 00:00:00

  • A Chemical Approach to Overcome Tyrosine Kinase Inhibitors Resistance: Learning from Chronic Myeloid Leukemia.

    abstract:BACKGROUND:The possibilities of treatment for oncological diseases are growing enormously in the last decades. Unfortunately, these developments have led to the onset of resistances with regards to the new treatments. This is particularly true if we face with the therapeutic field of Tyrosine Kinase Inhibitors (TKIs). ...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867325666180607092451

    authors: Zanforlin E,Zagotto G,Ribaudo G

    更新日期:2019-01-01 00:00:00

  • Endothelial cell adhesion molecules and cancer progression.

    abstract::The role of cell adhesion molecules (CAMs), such as intercellular cell adhesion molecule-1 (ICAM-1), vascular endothelial cell adhesion molecule-1 (VCAM-1), E-selectin, and P-selectin, has been studied extensively in the process of inflammation. These molecules are responsible for recruiting leukocytes onto the vascul...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986707779941032

    authors: Kobayashi H,Boelte KC,Lin PC

    更新日期:2007-01-01 00:00:00

  • Recent trends in the design, synthesis and biological exploration of β-lactams.

    abstract::Since the discovery of penicillin, natural and synthetic β-lactams have aroused great interest not only as sources of effective antibacterial agents but also as specific inhibitors of proteases responsible for various non-bacterial pathological processes. This interest was reflected in our review published in Current ...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/09298673113206660268

    authors: Veinberg G,Potorocina I,Vorona M

    更新日期:2014-01-01 00:00:00

  • Target-based drug discovery for malaria, leishmaniasis, and trypanosomiasis.

    abstract::Advances in combinatorial chemistry, high-throughput screening, and molecular modeling have revolutionized the process of drug discovery in the pharmaceutical industry. Drug discovery efforts for the primary protozoal parasitic diseases of the developing world, malaria, leishmaniasis, and trypanosomiasis, have also be...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867003374615

    authors: Werbovetz KA

    更新日期:2000-08-01 00:00:00

  • Nicotinamide adenine dinucleotide based therapeutics.

    abstract::Nicotinamide adenine dinucleotide (NAD), generally considered a key component involved in redox reactions, has been found to participate in an increasingly diverse range of cellular processes, including signal transduction, DNA repair, and post-translational protein modifications. In recent years, medicinal chemists h...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986708783885282

    authors: Chen L,Petrelli R,Felczak K,Gao G,Bonnac L,Yu JS,Bennett EM,Pankiewicz KW

    更新日期:2008-01-01 00:00:00

  • Dietary Polyphenols and Mitochondrial Function: Role in Health and Disease.

    abstract::Mitochondria are cytoplasmic double-membraned organelles that are involved in a myriad of key cellular regulatory processes. The loss of mitochondrial function is related to the pathogenesis of several human diseases. Over the last decades, an increasing number of studies have shown that dietary polyphenols can regula...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867324666170529101810

    authors: Teixeira J,Chavarria D,Borges F,Wojtczak L,Wieckowski MR,Karkucinska-Wieckowska A,Oliveira PJ

    更新日期:2019-01-01 00:00:00

  • Metal-based antimicrobial protease inhibitors.

    abstract::Limitations associated with the production cost, metabolic instability, side-effects, resistance and poor pharmacokinetics of organic protease inhibitors (PIs), which form an essential component of the front line HAART treatment for HIV, have fuelled efforts into finding novel, transition metal-based alternatives. Som...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867311320250008

    authors: Kellett A,Prisecaru A,Slator C,Molphy Z,McCann M

    更新日期:2013-01-01 00:00:00

  • Xanthones as potential antioxidants.

    abstract::Xanthones (dibenzo-γ-pyrones) constitutes an important class of oxygenated heterocycles and occur as secondary metabolites in plants and microorganisms. They are known for various biological activities such as antioxidant, monoamine oxidase inhibitor, antihypertensive, hepatoprotective, antithrombotic, antifungal and ...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/09298673113209990144

    authors: Panda SS,Chand M,Sakhuja R,Jain SC

    更新日期:2013-01-01 00:00:00

  • Review of cardiovascular effects of fluoxetine, a selective serotonin reuptake inhibitor, compared to tricyclic antidepressants.

    abstract::Fluoxetine is an antidepressant drug, a potent and specific inhibitor of serotonin reuptake (SSRI). Evidence suggests that being compared with tricyclic antidepressants, fluoxetine may cause significantly fewer anticholinergic, antihistaminergic and cardiotoxic side effects in the treatment of major depressive disorde...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:

    authors: Pacher P,Ungvari Z,Kecskemeti V,Furst S

    更新日期:1998-10-01 00:00:00

  • Regulators of serine/threonine protein phosphatases at the dawn of a clinical era?

    abstract::Reversible phosphorylation is a key mechanism for regulating the biological activity of many human proteins that affect a diverse array of cellular processes, including protein-protein interactions, gene transcription, cell-cycle progression and apoptosis. Once viewed as simple house keeping enzymes, recent studies ha...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867023368836

    authors: Honkanen RE,Golden T

    更新日期:2002-11-01 00:00:00

  • Hyaluronidase inhibitors: a biological and therapeutic perspective.

    abstract::The hyaluronidases (HAases) are a group of less extensively studied glycosidases distributed throughout the animal kingdom and are popularly known as 'spreading factors'. In recent years, HAases received much attention due to their ability to abruptly alter the hyaluronic acid (HA) homeostasis. HAases preferentially d...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986709788453078

    authors: Girish KS,Kemparaju K,Nagaraju S,Vishwanath BS

    更新日期:2009-01-01 00:00:00

  • Schwann cell transplantation for CNS repair.

    abstract::Demyelination occurs in several central nervous system (CNS) disorders, including multiple sclerosis, viral infection and spinal cord injury and can result in severe functional impairment. Therefore there is great interest in developing therapies promoting repair in CNS demyelinating diseases and trauma. Cell replacem...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986708783330593

    authors: Lavdas AA,Papastefanaki F,Thomaidou D,Matsas R

    更新日期:2008-01-01 00:00:00

  • Advances in Medicinal Chemistry from Analytical Perspectives.

    abstract:: ...

    journal_title:Current medicinal chemistry

    pub_type: 社论

    doi:10.2174/092986732533181024105316

    authors: Ozkan SA

    更新日期:2018-01-01 00:00:00

  • Therapeutic constituents and actions of Rubus species.

    abstract::Rubus species (family Rosaceae) have been cultivated for centuries for their fruits. These and other parts of the plants have been used traditionally for therapeutic purposes. This article highlights these and the potential they can offer. The constituents reported in the various species and those demonstrated to exhi...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867043365143

    authors: Patel AV,Rojas-Vera J,Dacke CG

    更新日期:2004-06-01 00:00:00

  • Pharmacotherapy of borderline personality disorder: a systematic review for publication purpose.

    abstract::Borderline Personality Disorder (BPD) is a common disorder in psychiatric practice and drugs are widely used in its treatment, targeting symptom clusters, such as affective dysregulation, impulsive-behavioural dyscontrol, and cognitive-perceptual symptoms. In last period, a growing number of studies on pharmacological...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986711796504682

    authors: Bellino S,Rinaldi C,Bozzatello P,Bogetto F

    更新日期:2011-01-01 00:00:00

  • Antisense oligonucleotides: the state of the art.

    abstract::The use of antisense oligonucleotides as therapeutic agents has generated considerable enthusiasm in the research and medical community. Antisense oligonucleotides as therapeutic agents were proposed as far back as in the 1970s when the antisense strategy was initially developed. Nonetheless, it has taken almost a qua...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867054864859

    authors: Aboul-Fadl T

    更新日期:2005-01-01 00:00:00