CEP-7055

A novel, orally active pan inhibitor of vascular endothelial growth factor receptor tyrosine kinases with potent antiangiogenic activity and antitumor efficacy in preclinical models

Bruce Ruggeri, Jasbir Singh, Diane Gingrich, Thelma Angeles, Mark Albom, Hong Chang, Candy Robinson, Kathryn Hunter, Pawel Dobrzanski, Susan Jones-Bolin, Lisa Aimone, Andres Klein-Szanto, Jean Marc Herbert, Francoise Bono, Paul Schaeffer, Pierre Casellas, Bernard Bourie, Roberto Pili, John Tod Isaacs, Mark Ator & 4 others Robert Hudkins, Jeffry Vaught, John Mallamo, Craig Dionne

Research output: Contribution to journalArticle

Abstract

Inhibition of the vascular endothelial growth factor VEGF-VEGF receptor (VEGF-R) kinase axes in the tumor angiogenic cascade is a promising therapeutic strategy in oncology. CEP-7055 is the fully synthetic orally active N, N-dimethyl glycine ester of CEP-5214, a C3-(isopropylmethoxy) fused pyrrolocarbazole with potent pan-VEGF-R kinase inhibitory activity. CEP-5214 demonstrates IC50 values of 18 nM, 12 nM, and 17 nM against human VEGF-R2/KDR kinase, VEGF-R1/FLT-1 kinase, and VEGF-R3/FLT-4 kinase, respectively, in biochemical kinase assays. CEP-5214 inhibited VEGF-stimulated VEGF-R2/KDR autophosphorylation in human umbilical vein endothelial cells (HUVECs) with an IC50 of ∼10 nM and demonstrated an equivalent inhibition of murine FLK-1 autophosphorylation in transformed SVR endothelial cells. Evaluation of the antiangiogenic activity of CEP-5214 revealed a dose-related inhibition of microvessel growth ex vivo in rat aortic ring explant cultures and in vitro on HUVEC capillary-tube formation on Matrigel at low nanomolar concentrations. The antiangiogenic activity of CEP-5214 in these bioassays was observed in the absence of apparent cytotoxicity. Single-dose p.o. or s.c. administration of CEP-7055 or CEP-5214 to CD-1 mice at 23.8 mg/kg/dose b.i.d. resulted in a reversible inhibition of VEGF-R2/FLK-1 phosphorylation in murine lung tissues. Administration p.o. of CEP-7055 at 2.57 to 23.8 mg/kg/dose b.i.d. resulted in dose-related reductions in neovascularization in vivo in porcine aortic endothelial cell (PAEC)-VEGF/basic fibroblast growth factor-Matrigel implants in nude mice (maximum, 82% inhibition), significant reductions in granuloma formation (30%) and granuloma vascularity (42%) in a murine chronic inflammation-induced angiogenesis model, and significant and sustained (6 h) inhibition of VEGF-induced plasma extravasation in rats, with an ED50 of 20 mg/kg/dose. Chronic p.o. administration of CEP-7055 at doses of 11.9 to 23.8 mg/kg/dose b.i.d. resulted in significant inhibition (50-90% maximum inhibition relative to controls) in the growth of a variety of established murine and human s.c. tumor xenografts in nude mice, including A375 melanomas, U251MG and U87MG glioblastomas, CALU-6 lung carcinoma, ASPC-1 pancreatic carcinoma, HT-29 and HCT-116 colon carcinomas, MCF-7 breast carcinomas, and SVR angiosarcomas. Significant antitumor efficacy was observed similarly against orthotopically implanted LNCaP human prostate carcinomas in male nude mice and orthotopically implanted renal carcinoma (RENCA) tumors in BALB/c mice, in terms of a significant reduction in the metastatic score and the extent of pulmonary metastases. These antitumor responses were associated with marked increases in tumor apoptosis, and significant reductions in intratumoral microvessel density (CD34 and Factor VIII staining) of 22-38% relative to controls depending on the specific tumor xenograft. The antitumor efficacy of chronic CEP-7055 administration was independent of initial tumor volume (in the ASPC-1 pancreatic carcinoma model) and reversible on withdrawal of treatment. Chronic p.o. administration of CEP-7055 in preclinical efficacy studies for periods of up to 65 days was well tolerated with no apparent toxicity or significant morbidity. Orally administered CEP-7055 has entered Phase I clinical trials in cancer patients.

Original languageEnglish (US)
Pages (from-to)5978-5991
Number of pages14
JournalCancer Research
Volume63
Issue number18
StatePublished - Sep 15 2003

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Vascular Endothelial Growth Factor Receptor
Protein-Tyrosine Kinases
Vascular Endothelial Growth Factor A
Phosphotransferases
Nude Mice
Carcinoma
Neoplasms
Human Umbilical Vein Endothelial Cells
Microvessels
Granuloma
Heterografts
Lung
Inhibitory Concentration 50
Endothelial Cells
N,N-dimethylglycine 3-(5,6,7,13-tetrahydro-9-((1-methylethoxy)methyl)-5-oxo-12H-indeno(2,1-a)pyrrolo(3,4-c)carbazol-12-yl)propyl ester
Clinical Trials, Phase I
Hemangiosarcoma
Factor VIII
Fibroblast Growth Factor 2
Glioblastoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

CEP-7055 : A novel, orally active pan inhibitor of vascular endothelial growth factor receptor tyrosine kinases with potent antiangiogenic activity and antitumor efficacy in preclinical models. / Ruggeri, Bruce; Singh, Jasbir; Gingrich, Diane; Angeles, Thelma; Albom, Mark; Chang, Hong; Robinson, Candy; Hunter, Kathryn; Dobrzanski, Pawel; Jones-Bolin, Susan; Aimone, Lisa; Klein-Szanto, Andres; Herbert, Jean Marc; Bono, Francoise; Schaeffer, Paul; Casellas, Pierre; Bourie, Bernard; Pili, Roberto; Isaacs, John Tod; Ator, Mark; Hudkins, Robert; Vaught, Jeffry; Mallamo, John; Dionne, Craig.

In: Cancer Research, Vol. 63, No. 18, 15.09.2003, p. 5978-5991.

Research output: Contribution to journalArticle

Ruggeri, B, Singh, J, Gingrich, D, Angeles, T, Albom, M, Chang, H, Robinson, C, Hunter, K, Dobrzanski, P, Jones-Bolin, S, Aimone, L, Klein-Szanto, A, Herbert, JM, Bono, F, Schaeffer, P, Casellas, P, Bourie, B, Pili, R, Isaacs, JT, Ator, M, Hudkins, R, Vaught, J, Mallamo, J & Dionne, C 2003, 'CEP-7055: A novel, orally active pan inhibitor of vascular endothelial growth factor receptor tyrosine kinases with potent antiangiogenic activity and antitumor efficacy in preclinical models', Cancer Research, vol. 63, no. 18, pp. 5978-5991.
Ruggeri, Bruce ; Singh, Jasbir ; Gingrich, Diane ; Angeles, Thelma ; Albom, Mark ; Chang, Hong ; Robinson, Candy ; Hunter, Kathryn ; Dobrzanski, Pawel ; Jones-Bolin, Susan ; Aimone, Lisa ; Klein-Szanto, Andres ; Herbert, Jean Marc ; Bono, Francoise ; Schaeffer, Paul ; Casellas, Pierre ; Bourie, Bernard ; Pili, Roberto ; Isaacs, John Tod ; Ator, Mark ; Hudkins, Robert ; Vaught, Jeffry ; Mallamo, John ; Dionne, Craig. / CEP-7055 : A novel, orally active pan inhibitor of vascular endothelial growth factor receptor tyrosine kinases with potent antiangiogenic activity and antitumor efficacy in preclinical models. In: Cancer Research. 2003 ; Vol. 63, No. 18. pp. 5978-5991.
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title = "CEP-7055: A novel, orally active pan inhibitor of vascular endothelial growth factor receptor tyrosine kinases with potent antiangiogenic activity and antitumor efficacy in preclinical models",
abstract = "Inhibition of the vascular endothelial growth factor VEGF-VEGF receptor (VEGF-R) kinase axes in the tumor angiogenic cascade is a promising therapeutic strategy in oncology. CEP-7055 is the fully synthetic orally active N, N-dimethyl glycine ester of CEP-5214, a C3-(isopropylmethoxy) fused pyrrolocarbazole with potent pan-VEGF-R kinase inhibitory activity. CEP-5214 demonstrates IC50 values of 18 nM, 12 nM, and 17 nM against human VEGF-R2/KDR kinase, VEGF-R1/FLT-1 kinase, and VEGF-R3/FLT-4 kinase, respectively, in biochemical kinase assays. CEP-5214 inhibited VEGF-stimulated VEGF-R2/KDR autophosphorylation in human umbilical vein endothelial cells (HUVECs) with an IC50 of ∼10 nM and demonstrated an equivalent inhibition of murine FLK-1 autophosphorylation in transformed SVR endothelial cells. Evaluation of the antiangiogenic activity of CEP-5214 revealed a dose-related inhibition of microvessel growth ex vivo in rat aortic ring explant cultures and in vitro on HUVEC capillary-tube formation on Matrigel at low nanomolar concentrations. The antiangiogenic activity of CEP-5214 in these bioassays was observed in the absence of apparent cytotoxicity. Single-dose p.o. or s.c. administration of CEP-7055 or CEP-5214 to CD-1 mice at 23.8 mg/kg/dose b.i.d. resulted in a reversible inhibition of VEGF-R2/FLK-1 phosphorylation in murine lung tissues. Administration p.o. of CEP-7055 at 2.57 to 23.8 mg/kg/dose b.i.d. resulted in dose-related reductions in neovascularization in vivo in porcine aortic endothelial cell (PAEC)-VEGF/basic fibroblast growth factor-Matrigel implants in nude mice (maximum, 82{\%} inhibition), significant reductions in granuloma formation (30{\%}) and granuloma vascularity (42{\%}) in a murine chronic inflammation-induced angiogenesis model, and significant and sustained (6 h) inhibition of VEGF-induced plasma extravasation in rats, with an ED50 of 20 mg/kg/dose. Chronic p.o. administration of CEP-7055 at doses of 11.9 to 23.8 mg/kg/dose b.i.d. resulted in significant inhibition (50-90{\%} maximum inhibition relative to controls) in the growth of a variety of established murine and human s.c. tumor xenografts in nude mice, including A375 melanomas, U251MG and U87MG glioblastomas, CALU-6 lung carcinoma, ASPC-1 pancreatic carcinoma, HT-29 and HCT-116 colon carcinomas, MCF-7 breast carcinomas, and SVR angiosarcomas. Significant antitumor efficacy was observed similarly against orthotopically implanted LNCaP human prostate carcinomas in male nude mice and orthotopically implanted renal carcinoma (RENCA) tumors in BALB/c mice, in terms of a significant reduction in the metastatic score and the extent of pulmonary metastases. These antitumor responses were associated with marked increases in tumor apoptosis, and significant reductions in intratumoral microvessel density (CD34 and Factor VIII staining) of 22-38{\%} relative to controls depending on the specific tumor xenograft. The antitumor efficacy of chronic CEP-7055 administration was independent of initial tumor volume (in the ASPC-1 pancreatic carcinoma model) and reversible on withdrawal of treatment. Chronic p.o. administration of CEP-7055 in preclinical efficacy studies for periods of up to 65 days was well tolerated with no apparent toxicity or significant morbidity. Orally administered CEP-7055 has entered Phase I clinical trials in cancer patients.",
author = "Bruce Ruggeri and Jasbir Singh and Diane Gingrich and Thelma Angeles and Mark Albom and Hong Chang and Candy Robinson and Kathryn Hunter and Pawel Dobrzanski and Susan Jones-Bolin and Lisa Aimone and Andres Klein-Szanto and Herbert, {Jean Marc} and Francoise Bono and Paul Schaeffer and Pierre Casellas and Bernard Bourie and Roberto Pili and Isaacs, {John Tod} and Mark Ator and Robert Hudkins and Jeffry Vaught and John Mallamo and Craig Dionne",
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T1 - CEP-7055

T2 - A novel, orally active pan inhibitor of vascular endothelial growth factor receptor tyrosine kinases with potent antiangiogenic activity and antitumor efficacy in preclinical models

AU - Ruggeri, Bruce

AU - Singh, Jasbir

AU - Gingrich, Diane

AU - Angeles, Thelma

AU - Albom, Mark

AU - Chang, Hong

AU - Robinson, Candy

AU - Hunter, Kathryn

AU - Dobrzanski, Pawel

AU - Jones-Bolin, Susan

AU - Aimone, Lisa

AU - Klein-Szanto, Andres

AU - Herbert, Jean Marc

AU - Bono, Francoise

AU - Schaeffer, Paul

AU - Casellas, Pierre

AU - Bourie, Bernard

AU - Pili, Roberto

AU - Isaacs, John Tod

AU - Ator, Mark

AU - Hudkins, Robert

AU - Vaught, Jeffry

AU - Mallamo, John

AU - Dionne, Craig

PY - 2003/9/15

Y1 - 2003/9/15

N2 - Inhibition of the vascular endothelial growth factor VEGF-VEGF receptor (VEGF-R) kinase axes in the tumor angiogenic cascade is a promising therapeutic strategy in oncology. CEP-7055 is the fully synthetic orally active N, N-dimethyl glycine ester of CEP-5214, a C3-(isopropylmethoxy) fused pyrrolocarbazole with potent pan-VEGF-R kinase inhibitory activity. CEP-5214 demonstrates IC50 values of 18 nM, 12 nM, and 17 nM against human VEGF-R2/KDR kinase, VEGF-R1/FLT-1 kinase, and VEGF-R3/FLT-4 kinase, respectively, in biochemical kinase assays. CEP-5214 inhibited VEGF-stimulated VEGF-R2/KDR autophosphorylation in human umbilical vein endothelial cells (HUVECs) with an IC50 of ∼10 nM and demonstrated an equivalent inhibition of murine FLK-1 autophosphorylation in transformed SVR endothelial cells. Evaluation of the antiangiogenic activity of CEP-5214 revealed a dose-related inhibition of microvessel growth ex vivo in rat aortic ring explant cultures and in vitro on HUVEC capillary-tube formation on Matrigel at low nanomolar concentrations. The antiangiogenic activity of CEP-5214 in these bioassays was observed in the absence of apparent cytotoxicity. Single-dose p.o. or s.c. administration of CEP-7055 or CEP-5214 to CD-1 mice at 23.8 mg/kg/dose b.i.d. resulted in a reversible inhibition of VEGF-R2/FLK-1 phosphorylation in murine lung tissues. Administration p.o. of CEP-7055 at 2.57 to 23.8 mg/kg/dose b.i.d. resulted in dose-related reductions in neovascularization in vivo in porcine aortic endothelial cell (PAEC)-VEGF/basic fibroblast growth factor-Matrigel implants in nude mice (maximum, 82% inhibition), significant reductions in granuloma formation (30%) and granuloma vascularity (42%) in a murine chronic inflammation-induced angiogenesis model, and significant and sustained (6 h) inhibition of VEGF-induced plasma extravasation in rats, with an ED50 of 20 mg/kg/dose. Chronic p.o. administration of CEP-7055 at doses of 11.9 to 23.8 mg/kg/dose b.i.d. resulted in significant inhibition (50-90% maximum inhibition relative to controls) in the growth of a variety of established murine and human s.c. tumor xenografts in nude mice, including A375 melanomas, U251MG and U87MG glioblastomas, CALU-6 lung carcinoma, ASPC-1 pancreatic carcinoma, HT-29 and HCT-116 colon carcinomas, MCF-7 breast carcinomas, and SVR angiosarcomas. Significant antitumor efficacy was observed similarly against orthotopically implanted LNCaP human prostate carcinomas in male nude mice and orthotopically implanted renal carcinoma (RENCA) tumors in BALB/c mice, in terms of a significant reduction in the metastatic score and the extent of pulmonary metastases. These antitumor responses were associated with marked increases in tumor apoptosis, and significant reductions in intratumoral microvessel density (CD34 and Factor VIII staining) of 22-38% relative to controls depending on the specific tumor xenograft. The antitumor efficacy of chronic CEP-7055 administration was independent of initial tumor volume (in the ASPC-1 pancreatic carcinoma model) and reversible on withdrawal of treatment. Chronic p.o. administration of CEP-7055 in preclinical efficacy studies for periods of up to 65 days was well tolerated with no apparent toxicity or significant morbidity. Orally administered CEP-7055 has entered Phase I clinical trials in cancer patients.

AB - Inhibition of the vascular endothelial growth factor VEGF-VEGF receptor (VEGF-R) kinase axes in the tumor angiogenic cascade is a promising therapeutic strategy in oncology. CEP-7055 is the fully synthetic orally active N, N-dimethyl glycine ester of CEP-5214, a C3-(isopropylmethoxy) fused pyrrolocarbazole with potent pan-VEGF-R kinase inhibitory activity. CEP-5214 demonstrates IC50 values of 18 nM, 12 nM, and 17 nM against human VEGF-R2/KDR kinase, VEGF-R1/FLT-1 kinase, and VEGF-R3/FLT-4 kinase, respectively, in biochemical kinase assays. CEP-5214 inhibited VEGF-stimulated VEGF-R2/KDR autophosphorylation in human umbilical vein endothelial cells (HUVECs) with an IC50 of ∼10 nM and demonstrated an equivalent inhibition of murine FLK-1 autophosphorylation in transformed SVR endothelial cells. Evaluation of the antiangiogenic activity of CEP-5214 revealed a dose-related inhibition of microvessel growth ex vivo in rat aortic ring explant cultures and in vitro on HUVEC capillary-tube formation on Matrigel at low nanomolar concentrations. The antiangiogenic activity of CEP-5214 in these bioassays was observed in the absence of apparent cytotoxicity. Single-dose p.o. or s.c. administration of CEP-7055 or CEP-5214 to CD-1 mice at 23.8 mg/kg/dose b.i.d. resulted in a reversible inhibition of VEGF-R2/FLK-1 phosphorylation in murine lung tissues. Administration p.o. of CEP-7055 at 2.57 to 23.8 mg/kg/dose b.i.d. resulted in dose-related reductions in neovascularization in vivo in porcine aortic endothelial cell (PAEC)-VEGF/basic fibroblast growth factor-Matrigel implants in nude mice (maximum, 82% inhibition), significant reductions in granuloma formation (30%) and granuloma vascularity (42%) in a murine chronic inflammation-induced angiogenesis model, and significant and sustained (6 h) inhibition of VEGF-induced plasma extravasation in rats, with an ED50 of 20 mg/kg/dose. Chronic p.o. administration of CEP-7055 at doses of 11.9 to 23.8 mg/kg/dose b.i.d. resulted in significant inhibition (50-90% maximum inhibition relative to controls) in the growth of a variety of established murine and human s.c. tumor xenografts in nude mice, including A375 melanomas, U251MG and U87MG glioblastomas, CALU-6 lung carcinoma, ASPC-1 pancreatic carcinoma, HT-29 and HCT-116 colon carcinomas, MCF-7 breast carcinomas, and SVR angiosarcomas. Significant antitumor efficacy was observed similarly against orthotopically implanted LNCaP human prostate carcinomas in male nude mice and orthotopically implanted renal carcinoma (RENCA) tumors in BALB/c mice, in terms of a significant reduction in the metastatic score and the extent of pulmonary metastases. These antitumor responses were associated with marked increases in tumor apoptosis, and significant reductions in intratumoral microvessel density (CD34 and Factor VIII staining) of 22-38% relative to controls depending on the specific tumor xenograft. The antitumor efficacy of chronic CEP-7055 administration was independent of initial tumor volume (in the ASPC-1 pancreatic carcinoma model) and reversible on withdrawal of treatment. Chronic p.o. administration of CEP-7055 in preclinical efficacy studies for periods of up to 65 days was well tolerated with no apparent toxicity or significant morbidity. Orally administered CEP-7055 has entered Phase I clinical trials in cancer patients.

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