Potent and Selective Triazole-Based Inhibitors of the Hypoxia-Inducible Factor Prolyl-Hydroxylases with Activity in the Murine Brain

被引：64

作者：

Chan, Mun Chiang ^{[1
,2
]}

Atasoylu, Onur ^{[1
]}

Hodson, Emma ^{[2
]}

Tumber, Anthony ^{[3
]}

Leung, Ivanhoe K. H. ^{[1
]}

Chowdhury, Rasheduzzaman ^{[1
]}

Gomez-Perez, Veronica ^{[1
]}

Demetriades, Marina ^{[1
]}

Rydzik, Anna M. ^{[1
]}

Holt-Martyn, James ^{[1
]}

Tian, Ya-Min ^{[2
]}

Bishop, Tammie ^{[2
]}

Claridge, Timothy D. W. ^{[1
]}

Kawamura, Akane ^{[1
]}

Pugh, Christopher W. ^{[2
]}

Ratcliffe, Peter J. ^{[2
]}

Schofield, Christopher J. ^{[1
]}

机构：

[1] Univ Oxford, Dept Chem, Chem Res Lab, Oxford OX1 3TA, England

[2] Univ Oxford, Ctr Cellular & Mol Physiol, Oxford OX1 3TA, England

[3] Univ Oxford, Target Discovery Inst, Oxford OX1 3TA, England

来源：

PLOS ONE | 2015年 / 10卷 / 07期

基金：

英国惠康基金;

关键词：

ANKYRIN REPEAT DOMAIN; FACTOR HIF; ASPARAGINYL HYDROXYLASE; BETA-HYDROXYLATION; STRUCTURAL BASIS; BINDING; SUBSTRATE; PROTEINS; TARGET; ALPHA;

D O I：

10.1371/journal.pone.0132004

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

As part of the cellular adaptation to limiting oxygen availability in animals, the expression of a large set of genes is activated by the upregulation of the hypoxia-inducible transcription factors (HIFs). Therapeutic activation of the natural human hypoxic response can be achieved by the inhibition of the hypoxia sensors for the HIF system, i.e. the HIF prolyl-hydroxylases (PHDs). Here, we report studies on tricyclic triazole-containing compounds as potent and selective PHD inhibitors which compete with the 2-oxoglutarate co-substrate. One compound (IOX4) induces HIF alpha in cells and in wildtype mice with marked induction in the brain tissue, revealing that it is useful for studies aimed at validating the upregulation of HIF for treatment of cerebral diseases including stroke.

引用

页数：17

共 54 条

[1] PHENIX: a comprehensive Python']Python-based system for macromolecular structure solution [J].

Adams, Paul D. ;

Afonine, Pavel V. ;

Bunkoczi, Gabor ;

Chen, Vincent B. ;

Davis, Ian W. ;

Echols, Nathaniel ;

Headd, Jeffrey J. ;

Hung, Li-Wei ;

Kapral, Gary J. ;

Grosse-Kunstleve, Ralf W. ;

McCoy, Airlie J. ;

Moriarty, Nigel W. ;

Oeffner, Robert ;

Read, Randy J. ;

Richardson, David C. ;

Richardson, Jane S. ;

Terwilliger, Thomas C. ;

Zwart, Peter H. .

ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2010, 66 :213-221

[2] Structural Basis for Inhibition of the Fat Mass and Obesity Associated Protein (FTO) [J].

Aik, WeiShen ;

Demetriades, Marina ;

Hamdan, Muhammad K. K. ;

Bagg, Eleanor. A. L. ;

Yeoh, Kar Kheng ;

Lejeune, Clarisse ;

Zhang, Zhihong ;

McDonough, Michael A. ;

Schofield, Christopher J. .

JOURNAL OF MEDICINAL CHEMISTRY, 2013, 56 (09) :3680-3688

[3] Role of the jelly-roll fold in substrate binding by 2-oxoglutarate oxygenases [J].

Aik, WeiShen ;

McDonough, Michael A. ;

Thalhammer, Armin ;

Chowdhury, Rasheduzzaman ;

Schofield, Christopher J. .

CURRENT OPINION IN STRUCTURAL BIOLOGY, 2012, 22 (06) :691-700

[4] Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor [J].

Appelhoff, RJ ;

Tian, YM ;

Raval, RR ;

Turley, H ;

Harris, AL ;

Pugh, CW ;

Ratcliffe, PJ ;

Gleadle, JM .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (37) :38458-38465

[5] Water-based ligand screening for paramagnetic metalloproteins [J].

Bertini, Ivano ;

Fragai, Marco ;

Luchinat, Claudio ;

Talluri, Eleonora .

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2008, 47 (24) :4533-4537

[6]

Bigge CF, 2004, PCT INT APPL, Patent No. 2003018553

[7] Carotid body hyperplasia and enhanced ventilatory responses to hypoxia in mice with heterozygous deficiency of PHD2 [J].

Bishop, Tammie ;

Talbot, Nick P. ;

Turner, Philip J. ;

Nicholls, Lynn G. ;

Pascual, Alberto ;

Hodson, Emma J. ;

Douglas, Gillian ;

Fielding, James W. ;

Smith, Thomas G. ;

Demetriades, Marina ;

Schofield, Christopher J. ;

Robbins, Peter A. ;

Pugh, Christopher W. ;

Buckler, Keith J. ;

Ratcliffe, Peter J. .

JOURNAL OF PHYSIOLOGY-LONDON, 2013, 591 (14) :3565-3577

[8] A conserved family of prolyl-4-hydroxylases that modify HIF [J].

Bruick, RK ;

McKnight, SL .

SCIENCE, 2001, 294 (5545) :1337-1340

[9] Crystallography & NMR system:: A new software suite for macromolecular structure determination [J].

Brunger, AT ;

Adams, PD ;

Clore, GM ;

DeLano, WL ;

Gros, P ;

Grosse-Kunstleve, RW ;

Jiang, JS ;

Kuszewski, J ;

Nilges, M ;

Pannu, NS ;

Read, RJ ;

Rice, LM ;

Simonson, T ;

Warren, GL .

ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1998, 54 :905-921

[10] Selective Small Molecule Probes for the Hypoxia Inducible Factor (HIF) Prolyl Hydroxylases [J].

Chowdhury, Rasheduzzaman ;

Candela-Lena, Jose Ignacio ;

Chan, Mun Chiang ;

Greenald, David Jeremy ;

Yeoh, Kar Kheng ;

Tian, Ya-Min ;

McDonough, Michael A. ;

Tumber, Anthony ;

Rose, Nathan R. ;

Conejo-Garcia, Ana ;

Demetriades, Marina ;

Mathavan, Sinnakaruppan ;

Kawamura, Akane ;

Lee, Myung Kyu ;

van Eeden, Freek ;

Pugh, Christopher W. ;

Ratciffe, Peter J. ;

Schofieldt, Christopher J. .

ACS CHEMICAL BIOLOGY, 2013, 8 (07) :1488-1496

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