Discovery of LY2457546: a multi-targeted anti-angiogenic kinase inhibitor with a novel spectrum of activity and exquisite potency in the acute myelogenous leukemia-Flt-3-internal tandem duplication mutant human tumor xenograft model

Abstract

LY2457546 is a potent and orally bioavailable inhibitor of multiple receptor tyrosine kinases involved in angiogenic and tumorigenic signalling. In biochemical and cellular assays, LY2457546 demonstrates potent activity against targets that include VEGFR2 (KDR), PDGFRβ, FLT-3, Tie-2 and members of the Eph family of receptors. With activities against both Tie2 and Eph receptors, LY2457546 possesses an activity profile that distinguishes it from multikinase inhibitors. When compared head to head with sunitinib, LY2457546 was more potent for inhibition of endothelial tube formation in an in vitro angiogenesis co-culture model with an intermittent treatment design. In vivo, LY2457546 inhibited VEGF-driven autophosphorylation of lung KDR in the mouse and rat in a dose and concentration dependent manner. LY2457546 was well tolerated and exhibited efficacy in a 13762 syngeneic rat mammary tumor model in both once and twice daily continuous dosing schedules and in mouse human tumor xenograft models of lung, colon, and prostate origin. Additionally, LY2457546 caused complete regression of well-established tumors in an acute myelogenous leukemia (AML) FLT3-ITD mutant xenograft tumor model. The observed efficacy that was displayed by LY2457546 in the AML FLT3-ITD mutant tumor model was superior to sunitinib when both were evaluated using equivalent doses normalized to in vivo inhibition of pKDR in mouse lung. LY2457546 was well tolerated in non-clinical toxicology studies conducted in rats and dogs. The majority of the toxicities observed were similar to those observed with other multi-targeted anti-angiogenic kinase inhibitors (MAKs) and included bone marrow hypocellularity, hair and skin depigmentation, cartilage dysplasia and lymphoid organ degeneration and necrosis. Thus, the unique spectrum of target activity, potent in vivo anti-tumor efficacy in a variety of rodent and human solid tumor models, exquisite potency against a clinically relevant model of AML, and non-clinical safety profile justify the advancement of LY2457546 into clinical testing.

Human Carboxylesterase-2 Hydrolyzes the Prodrug of Gemcitabine (LY2334737) and Confers Prodrug Sensitivity to Cancer Cells

“…A detailed protocol for the HCT-116 xenograft was published previously (25). HCT-116 transfectants (mock and 5 CES2 HCT-116 subclones) were initially evaluated for tumor growth and for stability of CES2 expression when grown in vivo.…”

Efficacy of Low-Dose Oral Metronomic Dosing of the Prodrug of Gemcitabine, LY2334737, in Human Tumor Xenografts

“…HCT-116 xenograft studies (11,27) included treatment with LY2334737 administered by oral gavage either as the free base in a vehicle of 1% sodium carboxymethylcellulose, 0.5% sodium lauryl sulfate, 0.05% antifoam, or as the salt of LY2334737 in a vehicle of 0.1 mol/L Na3P04, pH 6; the dose is reported as the free base. Gemcitabine.HCl was administered intraperitoneally (0.2 mL) every third day for a total of 4 doses.…”

“…24,28). Data for tumor volumes and body weights were analyzed by 2-way ANOVA statistics (27). Drug treatments were considered "well tolerated" if mean body weight loss of the treatment group was 15% or less and was not significantly lower than the vehicle control.…”

Targeting Eph receptors with peptides and small molecules: Progress and challenges

“…This is consistent with the selectivity profile observed for many of the kinase inhibitors targeting Eph receptors. For example, dasatinib and nilotinib were first identified as Src and Abl inhibitors but also potently target Eph receptors [57,58]. …”