Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor

Abstract

ABT-869 is a structurally novel, receptor tyrosine kinase (RTK) inhibitor that is a potent inhibitor of members of the vascular endothelial growth factor (VEGF) and plateletderived growth factor (PDGF) receptor families (e.g., KDR IC 50 = 4 nmol/L) but has much less activity (IC 50 s > 1 Mmol/L) against unrelated RTKs, soluble tyrosine kinases, or serine/threonine kinases. The inhibition profile of ABT-869 is evident in cellular assays of RTK phosphorylation (IC 50 = 2, 4, and 7 nmol/L for PDGFR-B, KDR, and CSF-1R, respectively) and VEGF-stimulated proliferation (IC 50 = 0.2 nmol/L for human endothelial cells). ABT-869 is not a general antiproliferative agent because, in most cancer cells, >1,000-fold higher concentrations of ABT-869 are required for inhibition of proliferation. However, ABT-869 exhibits potent antiproliferative and apoptotic effects on cancer cells whose proliferation is dependent on mutant kinases, such as FLT3. In vivo ABT-869 is effective orally in the mechanism-based murine models of VEGF-induced uterine edema (ED 50 = 0.5 mg/kg) and corneal angiogenesis (>50% inhibition, 15 mg/kg). In tumor growth studies, ABT-869 exhibits efficacy in human fibrosarcoma and breast, colon, and small cell lung carcinoma xenograft models (ED 50 = 1.5 -5 mg/kg, twice daily) and is also effective (>50% inhibition) in orthotopic breast and glioma models. Reduction in tumor size and tumor regression was observed in epidermoid carcinoma and leukemia xenograft models, respectively. In combination, ABT-869 produced at least additive effects when given with cytotoxic therapies. Based on pharmacokinetic analysis from tumor growth studies, efficacy correlated more strongly with time over a threshold value (cellular KDR IC 50 corrected for plasma protein binding = 0.08 Mg/mL, z7 hours) than with plasma area under the curve or C max . These results support clinical assessment of ABT-869 as a therapeutic agent for cancer. [Mol Cancer Ther 2006;5(4):995 -1006]

Axitinib for the Management of Metastatic Renal Cell Carcinoma

“…[33,[39][40][41][42][43][44][45] Additionally, studies carried out in vitro showed that axitinib did not significantly inhibit other receptor kinases that were tested, including colony-stimulating factor (CSF)-1R, fms-like tyrosine kinase (Flt)-3, fibroblast growth factor receptor (FGFR)-1, ret proto-oncogene (RET), epidermal growth factor receptor (EGFR), and met proto-oncogene encoding hepatocyte growth factor (c-Met). [32] …”

“…Data from a phase I two-way crossover study of axitinib alone or coadministered with ketoconazole (a potent CYP3A inhibitor) in healthy volunteers (n = 32) demonstrated that concurrent administration of ketoconazole increased axitinib plasma exposure (AUC ¥ ) and C max with approximate Relative potency of targeted agents in metastatic renal cell carcinoma (mRCC). [32,33,[39][40][41][42][43][44][45] IC 50 = concentration that produces 50% inhibition; VEGFR = vascular endothelial growth factor receptor. Reproduced from Bellmunt et al, [33] with permission.…”

Drug resistance in mutant FLT3-positive AML

“…Additional novel FLT3 inhibitors in early development include the N-(4-(3-amino-1H-indazol-4yl)phenyl-N1(2-fluoro-5-methylphenyl) urea ABT-869 (Albert et al, 2006;Shankar et al, 2007;Zhou et al, 2008), which is a multitargeted inhibitor with activity toward FLT3, PDGFR, KIT and KDR; the benzimidalzolequinoline CHIR-258 (TKI258; Chiron, Emeryville, CA, USA), which has among its targets FLT3, KIT, FMS, VEGFR and FGFR (Lopes de Menezes et al, 2005) and is a promising antimyeloma drug (Trudel et al, 2005) presently in Phase I clinical trials for multiple myeloma, mixed solid tumors and AML; the hydroxystyrylacrylonitrile LS104 (Kasper et al, 2008), which is in a Phase I clinical trial for patients with refractory/ relapsed hematological malignancies; and AP24534 (Ariad, Cambridge, MA, USA), a multitargeted kinase inhibitor with activity against FLT3, KIT and FGFR (Rivera et al, 2008), and which is in Phase I clinical trials for CML and other hematological malignancies. It is important to note that thus far, no selective FLT3 inhibitor has been developed that would allow the study of FLT3 exclusively as a target.…”

Linifanib

“…When given in combination with other therapies, linifanib produced at least additive effects. [18,19] Further in vitro studies demonstrated that linifanib at an IC 50 of 10 nmol/L inhibited growth of MV-4-11 cells (human acute myeloid leukemia cell line that expresses FLT3-ITD) and BAF3-ITD cells (murine B-cell line stably transfected with the FLT3-ITD). The drug was also effective against D835V, another FLT3 mutation, with an IC 50 of 100 nmol/L.…”