Inhibition of Tumor Angiogenesis and Growth by a Small-Molecule Multi-FGF Receptor Blocker with Allosteric Properties

被引：121

作者：

Bono, Francoise ^{[1
,2
]}

De Smet, Frederik ^{[3
,4
]}

Herbert, Corentin ^{[1
,2
]}

De Bock, Katrien ^{[3
,4
]}

Georgiadou, Maria ^{[3
,4
]}

Fons, Pierre ^{[1
,2
]}

Tjwa, Marc ^{[3
,4
]}

Alcouffe, Chantal ^{[1
,2
]}

Ny, Annelii ^{[3
,4
]}

Bianciotto, Marc ^{[1
,2
]}

Jonckx, Bart ^{[3
,4
]}

Murakami, Masahiro ^{[5
]}

Lanahan, Anthony A. ^{[5
]}

Michielsen, Christof ^{[6
]}

Sibrac, David ^{[1
,2
]}

Dol-Gleizes, Frederique ^{[1
,2
]}

Mazzone, Massimiliano ^{[3
,4
]}

Zacchigna, Serena ^{[3
,4
]}

Herault, Jean-Pascal ^{[1
,2
]}

Fischer, Christian ^{[3
,4
]}

Rigon, Patrice ^{[1
,2
]}

de Almodovar, Carmen Ruiz ^{[3
,4
]}

Claes, Filip ^{[3
,4
]}

Blanc, Isabelle ^{[1
,2
]}

Poesen, Koen ^{[3
,4
]}

Zhang, Jie ^{[6
]}

Segura, Inmaculada ^{[3
,4
]}

Gueguen, Genevieve ^{[1
,2
]}

Bordes, Marie-Francoise ^{[1
,2
]}

Lambrechts, Diether ^{[3
,4
]}

Broussy, Roselyne ^{[1
,2
]}

van de Wouwer, Marlies ^{[3
,4
]}

Michaux, Corinne ^{[1
,2
]}

Shimada, Toru ^{[9
]}

Jean, Isabelle ^{[1
,2
]}

Blacher, Silvia ^{[11
]}

Noel, Agnes ^{[11
]}

Motte, Patrick ^{[11
]}

Rom, Eran ^{[12
]}

Rakic, Jean-Marie ^{[10
]}

Katsuma, Susumu ^{[9
]}

Schaeffer, Paul ^{[1
,2
]}

Yayon, Avner ^{[12
]}

Van Schepdael, Ann ^{[6
]}

Schwalbe, Harald ^{[13
]}

Luigi Gervasio, Francesco ^{[14
]}

Carmeliet, Geert ^{[7
]}

Rozensky, Jef ^{[8
]}

Dewerchin, Mieke ^{[3
,4
]}

Simons, Michael ^{[5
]}

机构：

[1] Sanofi Rech, Early Candidate Dept, F-31036 Toulouse, France

[2] Sanofi Rech, Lead Generat & Candidate Realizat Dept, F-31036 Toulouse, France

[3] Univ Leuven, Dept Oncol, Vesalius Res Ctr, Lab Angiogenesis & Neurovasc Link, B-3000 Louvain, Belgium

[4] VIB, Vesalius Res Ctr, Lab Angiogenesis & Neurovasc Link, B-3000 Louvain, Belgium

[5] Yale Univ, Sch Med, Dept Internal Med, Sect Cardiovasc Med, New Haven, CT 06520 USA

[6] Katholieke Univ Leuven, Lab Pharmaceut Anal Pharmaceut & Pharmacol Sci, B-3000 Louvain, Belgium

[7] Katholieke Univ Leuven, Lab Clin & Expt Endocrinol, B-3000 Louvain, Belgium

[8] Katholieke Univ Leuven, Rega Inst, B-3000 Louvain, Belgium

[9] Univ Tokyo, Sch Agr & Life Sci, Dept Agr & Environm Biol, Tokyo 1138657, Japan

[10] CHU Sart Tilman, Univ Hosp, Dept Ophthalmol, B-4000 Liege, Belgium

[11] Univ Liege, GIGA, Lab Tumor & Dev Biol, B-4000 Liege, Belgium

[12] ProCore Ltd, IL-10400 Ness Ziona, Israel

[13] Goethe Univ Frankfurt, Ctr Biomol Magnet Resonance BMRZ, Inst Organ Chem & Chem Biol, D-60438 Frankfurt, Germany

[14] Spanish Natl Canc Res Ctr CNIO, Computat Biophys Grp, E-28029 Madrid, Spain

[15] Monash Univ, Monash Inst Pharmaceut Sci, Parkville, Vic 3052, Australia

来源：

CANCER CELL | 2013年 / 23卷 / 04期

基金：

英国医学研究理事会;

关键词：

PROTEIN-COUPLED RECEPTORS; FIBROBLAST; MODULATION; BINDING; VEGF; METASTASIS; THERAPY; DISEASE; CANCER; CELLS;

D O I：

10.1016/j.ccr.2013.02.019

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Receptor tyrosine kinases (RTK) are targets for anticancer drug development. To date, only RTK inhibitors that block orthosteric binding of ligands and substrates have been developed. Here, we report the pharmacologic characterization of the chemical SSR128129E (SSR), which inhibits fibroblast growth factor receptor (FGFR) signaling by binding to the extracellular FGFR domain without affecting orthosteric FGF binding. SSR exhibits allosteric properties, including probe dependence, signaling bias, and ceiling effects. Inhibition by SSR is highly conserved throughout the animal kingdom. Oral delivery of SSR inhibits arthritis and tumors that are relatively refractory to anti-vascular endothelial growth factor receptor-2 antibodies. Thus, orally active, extracellularly acting small-molecule modulators of RTKs with allosteric properties can be developed and may offer opportunities to improve anticancer treatment.

引用

页码：477 / 488

页数：12

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