The small molecule specific EphB4 kinase inhibitor NVP-BHG712 inhibits VEGF driven angiogenesis.
EphB4 and its cognitive ligand ephrinB2 play an important role in embryonic vessel development and vascular remodeling. In addition, several reports suggest that this receptor ligand pair is also involved in pathologic vessel formation in adults including tumor angiogenesis. Eph/ephrin signaling is a complex phenomena characterized by receptor forward signaling through the tyrosine kinase of the receptor and ephrin reverse signaling through various protein-protein interaction domains and phosphorylation motifs of the ephrin ligands. Therefore, interfering with EphR/ephrin signaling by the means of targeted gene ablation, soluble receptors, dominant negative mutants or antisense molecules often does not allow to discriminate between inhibition of Eph/ephrin forward and reverse signaling. We developed a specific small molecular weight kinase inhibitor of the EphB4 kinase, NVP-BHG712, which inhibits EphB4 kinase activity in the low nanomolar range in cellular assays showed high selectivity for targeting the EphB4 kinase when profiled against other kinases in biochemical as well as in cell based assays. Furthermore, NVP-BHG712 shows excellent pharmacokinetic properties and potently inhibits EphB4 autophosphorylation in tissues after oral administration. In vivo, NVP-BHG712 inhibits VEGF driven vessel formation, while it has only little effects on VEGF receptor (VEGFR) activity in vitro or in cellular assays. The data shown here suggest a close cross talk between the VEGFR and EphR signaling during vessel formation. In addition to its established function in vascular remodeling and endothelial arterio-venous differentiation, EphB4 forward signaling appears to be an important mediator of VEGF induced angiogenesis since inhibition of EphB4 forward signaling is sufficient to inhibit VEGF induced angiogenesis.
Martiny-Baron
Georg
G
Novartis Institutes for Biomedical Research, Expertise Platform Kinases, Novartis Campus, Fabrikstrasse 16, WJS152.1.72.2, 4056 Basel, Switzerland. georg.martiny-baron@novartis.com
Holzer
Philipp
P
Billy
Eric
E
Schnell
Christian
C
Brueggen
Joseph
J
Ferretti
Mireille
M
Schmiedeberg
Niko
N
Wood
Jeanette M
JM
Furet
Pascal
P
Imbach
Patricia
P
D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D001681:Biological Assay; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D011743:Pyrimidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D036224:Receptor, EphB4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology*; D012995:Solubility / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D020533:Angiogenesis Inhibitors; C558163:NVP BH6712; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D054852:Small Molecule Libraries; D042461:Vascular Endothelial Growth Factor A; D036224:Receptor, EphB4
Neoplasia. 2004 May-Jun;6(3):248-57
15153337
Am J Pathol. 2010 Apr;176(4):2029-38
20133814
Clin Chem. 1995 Sep;41(9):1391-7
7656455
Cancer Res. 2007 May 1;67(9):3994-7
17483308
Clin Cancer Res. 2009 Mar 1;15(5):1612-22
19223496
BMC Mol Biol. 2001;2:15
11801186
BMC Cancer. 2005 Sep 20;5:119
16171530
Ann Oncol. 2003 Feb;14(2):220-6
12562648
Invest Ophthalmol Vis Sci. 2005 Dec;46(12):4772-9
16303978
Cornea. 2007 Jun;26(5):569-78
17525654
Cell. 2001 Jan 12;104(1):57-69
11163240
Am J Pathol. 2006 Jul;169(1):279-93
16816380
FASEB J. 2005 Nov;19(13):1884-6
16166198
J Med Chem. 2009 Oct 22;52(20):6433-46
19788238
FASEB J. 2002 Jul;16(9):1126-8
12039842
Structure. 2006 Feb;14(2):321-30
16472751
Biochim Biophys Acta. 2010 Mar;1804(3):445-53
19922818
Cytokine Growth Factor Rev. 2002 Feb;13(1):75-85
11750881
Bioorg Med Chem Lett. 2008 May 1;18(9):2776-80
18434142
J Biol Chem. 2005 Jun 10;280(23):22445-53
15781448
Blood. 2006 Mar 15;107(6):2330-8
16322467
Development. 2002 Mar;129(6):1397-410
11880349
Cancer Res. 2009 Sep 15;69(18):7430-8
19738063
Cancer Cell. 2004 Mar;5(3):231-9
15050915
Cancer Res. 2000 Apr 15;60(8):2178-89
10786682
Exp Eye Res. 2006 Apr;82(4):664-73
16359662
Trends Cardiovasc Med. 2000 Jul;10(5):183-8
11282292
Cancer Res. 2005 Jun 1;65(11):4623-32
15930280
Cancer Res. 2006 Nov 15;66(22):10709-19
17090524
Mech Dev. 2003 Apr;120(4):511-6
12676328
Cell. 1998 May 29;93(5):741-53
9630219
Genes Dev. 1999 Feb 1;13(3):295-306
9990854
J Biol Chem. 2005 Apr 29;280(17):17301-11
15722342
Nat Cell Biol. 2006 Aug;8(8):815-25
16862147
Nature. 2010 May 27;465(7297):487-91
20445540
Bioorg Med Chem Lett. 2008 Nov 1;18(21):5717-21
18851911
Nature. 2005 Jun 23;435(7045):1126-30
15973414
Nature. 2000 Sep 14;407(6801):242-8
11001067
Am J Pathol. 2009 Jun;174(6):2388-99
19443703
Cancer. 2002 Feb 15;94(4):934-9
11920461
Bioorg Med Chem Lett. 2009 Dec 15;19(24):6991-5
19879134
Mol Cell. 1999 Sep;4(3):403-14
10518221
Nature. 2010 May 27;465(7297):483-6
20445537
Cell. 2008 Apr 4;133(1):38-52
18394988
Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5583-8
15067119