生物活性

• 靶点

  VEGFR3 IC50:13nM

  VEGFR2 IC50:13nM

  VEGFR1 IC50:34nM

• 描述VEGF/VEGFR (vascular endothelial growth factor/vascular endothelial growth factor receptor) pathway plays a key role in tumor angiogenesis by promotion of vascular and lymphatic endothelial, as well as survival, and invasion, thus resulting in neovascularization, tumor growth and metastasis. In addition, blockade of additional proangiogenic receptor tyrosine kinases, including PDGFR and FGFR, may improve long-term clinical outcomes. BIBF 1120 is a multi-RTKs inhibitor with IC50 values of 13nM, 13nM , 16nM , 26nM , 34nM , 37nM , 59nM , 65nM , 69nM , 108nM for VEGFR2, VEGFR3, LCK, FLT3, VEGFR1, FGFR2, PDGFRα, PDGFRβ, FGFR1, FGFR3 (measured by enzymatic assays), less potent to Src, Lyn and FGFR4 with IC50 values of 156nM , 195nM and 610nM, respectively. Treatment with BIBF 1120 resulted in cell proliferation and apoptosis (EC50<10nM) in HUVECs, HSMECs, as well as the downstream p-MAPK and p-AKT (0.1-1μM). Daily oral treatment with BIBF 1120 at dose of 100mg/kg for 5 days reduced vessel density by 76% in FaDu xenografts, as well as markedly reduced both Meca 32–positive and PDGFRβ-positive cells predominantly in the intratumoral compartment. Once daily oral administration of BIBF 1120 at dose of 50mg/kg and 100mg/kg inhibited tumor growth both in a model of human head and neck small cell carcinoma (FaDu cells) and in a human renal cancer model (Caki-1 cells)^[1].
• 作用机制BIBF 1120 is ATP-competitive proangiogenic receptor tyrosine kinase inhibitor, which can bound in the active site of the VEGFR-2.^[1]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  A549	2/5 μM	Function Assay	24 h	has a general EMT reversal effect	26061747
  A549	0.01–5 μM	Function Assay	24 h	induces SFTPD mRNA expression dose dependently	25843005
  A549	0.01–5 μM	Function Assay	72 h	enhances SP-D protein expression in a dose-dependent manner at concentrations of up to 5 μM	25843005

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• 动物研究
  剂量	Mice: 50 mg/kg[2] (p.o.), 3 mg/kg - 100 mg/kg[3] (p.o.); 5 mg/kg[4] (i.p.) Rat: 25 mg/kg - 100 mg/kg[1] (p.o.)
  给药途径	p.o., i.p.
  动物药代数据	Animal Mice[5] Rats[5] Monkeys[5] Dose 50 mg/kg 50 mg/kg (p.o.) 2 mg/kg (i.v.) 40 mg/kg (p.o., cynomolgus monkey) 5 mg/kg (i.v., cynomolgus monkey) Administration p.o. p.o. i.v. p.o. i.v. MRT 5.19 h 3.25 h (i.v.) 3.82 h (i.v.) F 11.9% (p.o.) 13.2% (p.o.) T1/2 5.15 h 3.95 h (i.v.) 5.95 h (i.v.) AUC 2720 ng·h/ml 375 ng·h/ml (p.o.) 181 ng·h/ml (i.v.) 2390 ng·h/ml (p.o.) 2260 ng·h/ml (i.v.) CL 202 ml/min/kg (i.v.) 37.5 ml/min/kg (i.v.) Cmax 547 ng/ml 105 ng/ml (p.o.) 124 ng/ml (i.v.) 175 ng/ml (p.o.) 1300 ng/ml (i.v.) Protein bound (%) 92.9% (p.o.) Protein binding (free drug %) 0.972 98.5% (p.o.) Vss 41.2 L/kg (i.v.) 8.64 L/kg (i.v.)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT03361319	NSCLC, Recurrent ... more >> Adenocarcinoma of Lung Collapse <<	Phase 1 Phase 2	Not yet recruiting	January 2022	-
  NCT02863055	Malignant Pleural Mesothelioma	Phase 2	Recruiting	October 2020	Belgium ... more >> UZ Antwerpen Recruiting Antwerpen, Belgium Contact: Jan Van Meerbeeck, prof          UZ Gent Recruiting Gent, Belgium Contact: Veerle Surmont, Prof          Italy Ospedale San Paolo Recruiting Milan, Italy Contact: Andrea Luciani, Dr          United Kingdom Manchester University NHS Foundation Trust - UHSM-Wythenshawe Hospital Recruiting Wythenshawe, Manchester, United Kingdom, M23 9LT Principal Investigator: Paul Taylor          Royal Marsden Hospital Recruiting Chelsea, United Kingdom Contact: Sanjay Popat, Dr          Royal Marsden Hospital - Kingston Recruiting Kingston, United Kingdom Contact: Sanjay Popat, Dr          Sheffield Teaching Hospitals NHS Foundation Trust - Weston Park Hospital Recruiting Sheffield, United Kingdom Contact: Robin Young, Dr          NHS South Tyneside-South Tyneside District Hospital Recruiting South Shields, United Kingdom Contact: Rhona McMenemin, Dr          Royal Marsden Hospital Recruiting Sutton, United Kingdom Contact: Sanjay Popat, Dr Collapse <<
  NCT02597933	Scleroderma, Systemic	Phase 3	Completed	-	-

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• 参考文献

• [1] Hilberg F, Roth GJ, et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008 Jun 15;68(12):4774-82.

  [2] Roth GJ, Heckel A, et al. Design, synthesis, and evaluation of indolinones as triple angiokinase inhibitors and the discovery of a highly specific 6-methoxycarbonyl-substituted indolinone (BIBF 1120). J Med Chem. 2009 Jul 23;52(14):4466-80.

  [3] Wollin L, Maillet I, et al. Antifibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor nintedanib in experimental models of lung fibrosis. J Pharmacol Exp Ther. 2014 May;349(2):209-20.

  [4] Öztürk Akcora B, Storm G, et al. Tyrosine kinase inhibitor BIBF1120 ameliorates inflammation, angiogenesis and fibrosis in CCl4-induced liver fibrogenesis mouse model. Sci Rep. 2017 Mar 14;7:44545.

  [5] Nintedanib

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