Structure-Activity Relationship Studies and Molecular Modeling of Naphthalene-Based Sphingosine Kinase 2 Inhibitors

被引：19

作者：

Congdon, Molly D. ^{[1
]}

Kharel, Yugesh ^{[4
]}

Brown, Anne M. ^{[2
]}

Lewis, Stephanie N. ^{[2
]}

Bevan, David R. ^{[2
]}

Lynch, Kevin R. ^{[4
]}

Santos, Webster L. ^{[1
,3
]}

机构：

[1] Virginia Tech, Dept Chem, Blacksburg, VA 24061 USA

[2] Virginia Tech, Dept Biochem, Blacksburg, VA 24061 USA

[3] Virginia Tech, Ctr Drug Discovery, Blacksburg, VA 24061 USA

[4] Univ Virginia, Dept Pharmacol, Charlottesville, VA 22908 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2016年 / 7卷 / 03期

关键词：

Sphingosine; sphingosine-1; phosphate; sphingosine kinase; structure-activity relationship; molecular docking; ORAL FINGOLIMOD; SPHINGOSINE-1-PHOSPHATE; 1-PHOSPHATE; CANCER; TYPE-2; AXIS;

D O I：

10.1021/acsmedchemlett.5b00304

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The two isoforms of sphingosine kinase (SphK1 and SphK2) are the only enzymes that phosphorylate sphingosine to sphingosine-1-phosphate (S1P), which is a pleiotropic lipid mediator involved in a broad range of cellular processes including migration, proliferation, and inflammation. SphKs are targets for various diseases such as cancer, fibrosis, and Alzheimer's and sickle cell disease. Herein, we disclose the structure activity profile of naphthalene-containing SphK inhibitors and molecular modeling studies that reveal a key molecular switch that controls SphK selectivity.

引用

页码：229 / 234

页数：6

共 29 条

[1] Antiestrogenic Effects of the Novel Sphingosine Kinase-2 Inhibitor ABC294640 [J].

Antoon, James W. ;

White, Martin D. ;

Meacham, William D. ;

Slaughter, Evelyn M. ;

Muir, Shannon E. ;

Elliott, Steven ;

Rhodes, Lyndsay V. ;

Ashe, Hasina B. ;

Wiese, Thomas E. ;

Smith, Charles D. ;

Burow, Matthew E. ;

Beckman, Barbara S. .

ENDOCRINOLOGY, 2010, 151 (11) :5124-5135

[2] A Novel Sphingosine Kinase Inhibitor Induces Autophagy in Tumor Cells [J].

Beljanski, Vladimir ;

Knaak, Christian ;

Smith, Charles D. .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2010, 333 (02) :454-464

[3] Second generation S1P pathway modulators: Research strategies and clinical developments [J].

Bigaud, Marc ;

Guerini, Danilo ;

Billich, Andreas ;

Bassilana, Frederic ;

Brinkmann, Volker .

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, 2014, 1841 (05) :745-758

[4] Oral Fingolimod or Intramuscular Interferon for Relapsing Multiple Sclerosis [J].

Cohen, Jeffrey A. ;

Barkhof, Frederik ;

Comi, Giancarlo ;

Hartung, Hans-Peter ;

Khatri, Bhupendra O. ;

Montalban, Xavier ;

Pelletier, Jean ;

Capra, Ruggero ;

Gallo, Paolo ;

Izquierdo, Guillermo ;

Tiel-Wilck, Klaus ;

de Vera, Ana ;

Jin, James ;

Stites, Tracy ;

Wu, Stacy ;

Aradhye, Shreeram ;

Kappos, Ludwig .

NEW ENGLAND JOURNAL OF MEDICINE, 2010, 362 (05) :402-415

[5] Structure-activity relationship studies of the lipophilic tail region of sphingosine kinase 2 inhibitors [J].

Congdon, Molly D. ;

Childress, Elizabeth S. ;

Patwardhan, Neeraj N. ;

Gumkowski, James ;

Morris, Emily A. ;

Kharel, Yugesh ;

Lynch, Kevin R. ;

Santos, Webster L. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2015, 25 (21) :4956-4960

[6] Pharmacology and Antitumor Activity of ABC294640, a Selective Inhibitor of Sphingosine Kinase-2 [J].

French, Kevin J. ;

Zhuang, Yan ;

Maines, Lynn W. ;

Gao, Peng ;

Wang, Wenxue ;

Beljanski, Vladimir ;

Upson, John J. ;

Green, Cecelia L. ;

Keller, Staci N. ;

Smith, Charles D. .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2010, 333 (01) :129-139

[7] A Placebo-Controlled Trial of Oral Fingolimod in Relapsing Multiple Sclerosis [J].

Kappos, Ludwig ;

Radue, Ernst-Wilhelm ;

O'Connor, Paul ;

Polman, Chris ;

Hohlfeld, Reinhard ;

Calabresi, Peter ;

Selmaj, Krzysztof ;

Agoropoulou, Catherine ;

Leyk, Malgorzata ;

Zhang-Auberson, Lixin ;

Burtin, Pascale .

NEW ENGLAND JOURNAL OF MEDICINE, 2010, 362 (05) :387-401

[8] Sphingosine Kinase 2 Inhibition and Blood Sphingosine 1-Phosphate Levels [J].

Kharel, Yugesh ;

Morris, Emily A. ;

Congdon, Molly D. ;

Thorpe, Steven B. ;

Tomsig, Jose L. ;

Santos, Webster L. ;

Lynch, Kevin R. .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2015, 355 (01) :23-31

[9] Sphingosine kinase type 2 inhibition elevates circulating sphingosine 1-phosphate [J].

Kharel, Yugesh ;

Raje, Mithun ;

Gao, Ming ;

Gellett, Amanda M. ;

Tomsig, Jose L. ;

Lynch, Kevin R. ;

Santos, Webster L. .

BIOCHEMICAL JOURNAL, 2012, 447 :149-157

[10] A rapid assay for assessment of sphingosine kinase inhibitors and substrates [J].

Kharel, Yugesh ;

Mathews, Thomas P. ;

Kennedy, Andrew J. ;

Houck, Joseph D. ;

Macdonald, Timothy L. ;

Lynch, Kevin R. .

ANALYTICAL BIOCHEMISTRY, 2011, 411 (02) :230-235

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