Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties

Francesco Bono, Frederik De Smet, Corentin Herbert, Katrien De Bock, Maria Georgiadou, Pierre Fons, Marc Tjwa, Chantal Alcouffe, Annelii Ny, Marc Bianciotto, Bart Jonckx, Masahiro Murakami, Anthony A Lanahan, Christof Michielsen, David Sibrac, Frederique Dol-Gleizes, Massimiliano Mazzone, Serena Zacchigna, Jean-Pascal Herault, Christian Fischer & 33 others Patrice Rigon, Carmen Ruiz de Almodovar, Filip Claes, Isabelle Blanc, Koen Poesen, Zie Zhang, Immaculada Segura, Genevieve Gueguen, Marie-Francoise Bordes, Diether Lambrechts, Roselyne Broussy, Marlies van de Wouwer, Corinne Michaux, Toru Shimada, Isabelle Jean, Silvia Blacher, Agnes Noel, Patrick Motte, Eran Rom, Jean-Marie Rakic, Susumu Katsuma, Paul Schaeffer, Avner Yayon, Ann Van Schepdael, Harald Schwalbe, Francesco L Gervasio, Geert Carmeliet, Jef Rozensky, Mieke Dewerchin, Michael Simons, Arthur Christopoulos, Jean-Marc Herbert, Peter Carmeliet

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)477 - 488
Number of pages12
JournalCancer Cell
Volume23
Issue number4
DOIs
Publication statusPublished - 2013

Cite this

Bono, F., De Smet, F., Herbert, C., De Bock, K., Georgiadou, M., Fons, P., ... Carmeliet, P. (2013). Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties. Cancer Cell, 23(4), 477 - 488. https://doi.org/10.1016/j.ccr.2013.02.019
Bono, Francesco ; De Smet, Frederik ; Herbert, Corentin ; De Bock, Katrien ; Georgiadou, Maria ; Fons, Pierre ; Tjwa, Marc ; Alcouffe, Chantal ; Ny, Annelii ; Bianciotto, Marc ; Jonckx, Bart ; Murakami, Masahiro ; Lanahan, Anthony A ; Michielsen, Christof ; Sibrac, David ; Dol-Gleizes, Frederique ; Mazzone, Massimiliano ; Zacchigna, Serena ; Herault, Jean-Pascal ; Fischer, Christian ; Rigon, Patrice ; Ruiz de Almodovar, Carmen ; Claes, Filip ; Blanc, Isabelle ; Poesen, Koen ; Zhang, Zie ; Segura, Immaculada ; Gueguen, Genevieve ; Bordes, Marie-Francoise ; Lambrechts, Diether ; Broussy, Roselyne ; van de Wouwer, Marlies ; Michaux, Corinne ; Shimada, Toru ; Jean, Isabelle ; Blacher, Silvia ; Noel, Agnes ; Motte, Patrick ; Rom, Eran ; Rakic, Jean-Marie ; Katsuma, Susumu ; Schaeffer, Paul ; Yayon, Avner ; Van Schepdael, Ann ; Schwalbe, Harald ; Gervasio, Francesco L ; Carmeliet, Geert ; Rozensky, Jef ; Dewerchin, Mieke ; Simons, Michael ; Christopoulos, Arthur ; Herbert, Jean-Marc ; Carmeliet, Peter. / Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties. In: Cancer Cell. 2013 ; Vol. 23, No. 4. pp. 477 - 488.
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title = "Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties",
abstract = "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.",
author = "Francesco Bono and {De Smet}, Frederik and Corentin Herbert and {De Bock}, Katrien and Maria Georgiadou and Pierre Fons and Marc Tjwa and Chantal Alcouffe and Annelii Ny and Marc Bianciotto and Bart Jonckx and Masahiro Murakami and Lanahan, {Anthony A} and Christof Michielsen and David Sibrac and Frederique Dol-Gleizes and Massimiliano Mazzone and Serena Zacchigna and Jean-Pascal Herault and Christian Fischer and Patrice Rigon and {Ruiz de Almodovar}, Carmen and Filip Claes and Isabelle Blanc and Koen Poesen and Zie Zhang and Immaculada Segura and Genevieve Gueguen and Marie-Francoise Bordes and Diether Lambrechts and Roselyne Broussy and {van de Wouwer}, Marlies and Corinne Michaux and Toru Shimada and Isabelle Jean and Silvia Blacher and Agnes Noel and Patrick Motte and Eran Rom and Jean-Marie Rakic and Susumu Katsuma and Paul Schaeffer and Avner Yayon and {Van Schepdael}, Ann and Harald Schwalbe and Gervasio, {Francesco L} and Geert Carmeliet and Jef Rozensky and Mieke Dewerchin and Michael Simons and Arthur Christopoulos and Jean-Marc Herbert and Peter Carmeliet",
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Bono, F, De Smet, F, Herbert, C, De Bock, K, Georgiadou, M, Fons, P, Tjwa, M, Alcouffe, C, Ny, A, Bianciotto, M, Jonckx, B, Murakami, M, Lanahan, AA, Michielsen, C, Sibrac, D, Dol-Gleizes, F, Mazzone, M, Zacchigna, S, Herault, J-P, Fischer, C, Rigon, P, Ruiz de Almodovar, C, Claes, F, Blanc, I, Poesen, K, Zhang, Z, Segura, I, Gueguen, G, Bordes, M-F, Lambrechts, D, Broussy, R, van de Wouwer, M, Michaux, C, Shimada, T, Jean, I, Blacher, S, Noel, A, Motte, P, Rom, E, Rakic, J-M, Katsuma, S, Schaeffer, P, Yayon, A, Van Schepdael, A, Schwalbe, H, Gervasio, FL, Carmeliet, G, Rozensky, J, Dewerchin, M, Simons, M, Christopoulos, A, Herbert, J-M & Carmeliet, P 2013, 'Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties' Cancer Cell, vol. 23, no. 4, pp. 477 - 488. https://doi.org/10.1016/j.ccr.2013.02.019

Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties. / Bono, Francesco; De Smet, Frederik; Herbert, Corentin; De Bock, Katrien; Georgiadou, Maria; Fons, Pierre; Tjwa, Marc; Alcouffe, Chantal; Ny, Annelii; Bianciotto, Marc; Jonckx, Bart; Murakami, Masahiro; Lanahan, Anthony A; Michielsen, Christof; Sibrac, David; Dol-Gleizes, Frederique; Mazzone, Massimiliano; Zacchigna, Serena; Herault, Jean-Pascal; Fischer, Christian; Rigon, Patrice; Ruiz de Almodovar, Carmen; Claes, Filip; Blanc, Isabelle; Poesen, Koen; Zhang, Zie; Segura, Immaculada; Gueguen, Genevieve; Bordes, Marie-Francoise; Lambrechts, Diether; Broussy, Roselyne; van de Wouwer, Marlies; Michaux, Corinne; Shimada, Toru; Jean, Isabelle; Blacher, Silvia; Noel, Agnes; Motte, Patrick; Rom, Eran; Rakic, Jean-Marie; Katsuma, Susumu; Schaeffer, Paul; Yayon, Avner; Van Schepdael, Ann; Schwalbe, Harald; Gervasio, Francesco L; Carmeliet, Geert; Rozensky, Jef; Dewerchin, Mieke; Simons, Michael; Christopoulos, Arthur; Herbert, Jean-Marc; Carmeliet, Peter.

In: Cancer Cell, Vol. 23, No. 4, 2013, p. 477 - 488.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties

AU - Bono, Francesco

AU - De Smet, Frederik

AU - Herbert, Corentin

AU - De Bock, Katrien

AU - Georgiadou, Maria

AU - Fons, Pierre

AU - Tjwa, Marc

AU - Alcouffe, Chantal

AU - Ny, Annelii

AU - Bianciotto, Marc

AU - Jonckx, Bart

AU - Murakami, Masahiro

AU - Lanahan, Anthony A

AU - Michielsen, Christof

AU - Sibrac, David

AU - Dol-Gleizes, Frederique

AU - Mazzone, Massimiliano

AU - Zacchigna, Serena

AU - Herault, Jean-Pascal

AU - Fischer, Christian

AU - Rigon, Patrice

AU - Ruiz de Almodovar, Carmen

AU - Claes, Filip

AU - Blanc, Isabelle

AU - Poesen, Koen

AU - Zhang, Zie

AU - Segura, Immaculada

AU - Gueguen, Genevieve

AU - Bordes, Marie-Francoise

AU - Lambrechts, Diether

AU - Broussy, Roselyne

AU - van de Wouwer, Marlies

AU - Michaux, Corinne

AU - Shimada, Toru

AU - Jean, Isabelle

AU - Blacher, Silvia

AU - Noel, Agnes

AU - Motte, Patrick

AU - Rom, Eran

AU - Rakic, Jean-Marie

AU - Katsuma, Susumu

AU - Schaeffer, Paul

AU - Yayon, Avner

AU - Van Schepdael, Ann

AU - Schwalbe, Harald

AU - Gervasio, Francesco L

AU - Carmeliet, Geert

AU - Rozensky, Jef

AU - Dewerchin, Mieke

AU - Simons, Michael

AU - Christopoulos, Arthur

AU - Herbert, Jean-Marc

AU - Carmeliet, Peter

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

UR - http://www.sciencedirect.com/science/article/pii/S1535610813000755

U2 - 10.1016/j.ccr.2013.02.019

DO - 10.1016/j.ccr.2013.02.019

M3 - Article

VL - 23

SP - 477

EP - 488

JO - Cancer Cell

JF - Cancer Cell

SN - 1535-6108

IS - 4

ER -