Motesanib [N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide]
is a potent, orally bioavailable, ATP-competitive nicotinamide-based inhibitor
of human VEGFR2 when tested using in
vitro kinase assays. Motesanib has broad activity against the human VEGFR
family, including VEGFR1, VEGFR2, and VEGFR3 (IC50 = 2 ± 0.7, 3 ±
0.5, and 6 ± 4 nM, respectively) and displays similar activity against human
Kit (IC50 = 8 ± 2 nM). The compound also displays activity against
PDGFR (IC50 = 84 ± 33 nM) and Ret (IC50 = 59 ± 4nM),
although the potency was reduced ~10-fold relative to the VEGFR family. The
compound is highly selective against a broad range of ~47 other kinases tested,
including EGFR, Src, and p38 kinase (IC50 greater than 3 uM) [1].
The selectivity of Motesanib was preserved in cellular assays.
Potent inhibition of receptor phosphorylation and functional responses was
observed in biologically relevant cells. Motesanib potently inhibited
VEGF-induced but not bFGF-induced proliferation of HUVECs with IC50
values of 10 nM and greater than 3 uM, respectively. Similarly, Motesanib potently
inhibited both PDGF-induced proliferation and SCF-induced c-kit phosphorylation
with IC50 values of 207 and 37 nM, respectively. Motesanib displayed
no activity against unrelated kinases as evidenced by the lack of activity
against EGF-induced EGFR phosphorylation in A431 cells (IC50, greater
than 25 uM). Importantly, incubation of A431 tumor cells for 3 days with up to
25 µM, Motesanib did not affect their viability as determined by Alamar Blue
uptake [1].
The activity of Motesanib is as follows:
IC50 (VEGFR1 enzyme assay) = 2 ± 0.7 nM
IC50 (VEGFR2 enzyme assay) = 3 ± 0.5 nM
IC50 (VEGFR3 enzyme assay) = 6 ± 4 nM
IC50 (KIT enzyme assay) = 8 ± 2 nM
Common Name: Motesanib
Synonyms: AMG 706; AMG-706; AMG706
IUPAC Name: N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide
CAS Number: 453562-69-1; 857876-30-3 (diphosphate)
Mechanism of Action: Kinase Inhibitor; pan-VEGFR Inhibitor; VEGFR Inhibitor
Indication: Various Cancers; Solid Tumors
Development Stage: Phase III
Company: Amgen/Takeda
Increased endothelial cell apoptosis in association with decreased blood vessel area were the first temporal events observed following administration of Motesanib. This was followed by significant increases in tumor cell apoptosis. The sequence of these observations is consistent with targeting of tumor-associated endothelial cells and blood vessels as a primary mechanism of the antitumor activity of Motesanib in the model systems explored.
Increased endothelial cell apoptosis in association with decreased blood vessel area were the first temporal events observed following administration of Motesanib. This was followed by significant increases in tumor cell apoptosis. The sequence of these observations is consistent with targeting of tumor-associated endothelial cells and blood vessels as a primary mechanism of the antitumor activity of Motesanib in the model systems explored.
References:
1. Polverino, A.; et. al. AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts. Cancer Res 2006, 66(17), 8715-8721.
