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 IC(50) 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 IC (50) of approximately 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 ED(50) 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.
authors.affiliation: Department of Oncology, Cephalon, Inc., West Chester, Pennsylvania 19380, USA. bruggeri@cephalon.com
authors.forename: Bruce
authors.initials: B
authors.lastname: Ruggeri
authors.forename: Jasbir
authors.initials: J
authors.lastname: Singh
authors.forename: Diane
authors.initials: D
authors.lastname: Gingrich
authors.forename: Thelma
authors.initials: T
authors.lastname: Angeles
authors.forename: Mark
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authors.lastname: Albom
authors.forename: Shi
authors.initials: S
authors.lastname: Yang
authors.forename: Hong
authors.initials: H
authors.lastname: Chang
authors.forename: Candy
authors.initials: C
authors.lastname: Robinson
authors.forename: Kathryn
authors.initials: K
authors.lastname: Hunter
authors.forename: Pawel
authors.initials: P
authors.lastname: Dobrzanski
authors.forename: Susan
authors.initials: S
authors.lastname: Jones-Bolin
authors.forename: Sonya
authors.initials: S
authors.lastname: Pritchard
authors.forename: Lisa
authors.initials: L
authors.lastname: Aimone
authors.forename: Andres
authors.initials: A
authors.lastname: Klein-Szanto
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Herbert
authors.forename: Francoise
authors.initials: F
authors.lastname: Bono
authors.forename: Paul
authors.initials: P
authors.lastname: Schaeffer
authors.forename: Pierre
authors.initials: P
authors.lastname: Casellas
authors.forename: Bernard
authors.initials: B
authors.lastname: Bourie
authors.forename: Roberto
authors.initials: R
authors.lastname: Pili
authors.forename: John
authors.initials: J
authors.lastname: Isaacs
authors.forename: Mark
authors.initials: M
authors.lastname: Ator
authors.forename: Robert
authors.initials: R
authors.lastname: Hudkins
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Vaught
authors.forename: John
authors.initials: J
authors.lastname: Mallamo
authors.forename: Craig
authors.initials: C
authors.lastname: Dionne
mesh_terms: D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002227:Carbazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000201:enzymology; D010766:Phosphorylation; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C479233:3-(5,6,7,13-tetrahydro-9-((1-methylethoxy)methyl)-5-oxo-12H-indeno(2,1-a)pyrrolo(3,4-c)carbazol-12-yl)propanol; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D002227:Carbazoles; D004791:Enzyme Inhibitors; C479232: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; D011355:Prodrugs; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3