1.Dose study of the multikinase inhibitor, LY2457546, in patients with relapsed acute myeloid leukemia to assess safety, pharmacokinetics, and pharmacodynamics.
Wacheck V1, Lahn M, Dickinson G, Füreder W, Meyer R, Herndlhofer S, Füreder T, Dorfner G, Pillay S, André V, Burkholder TP, Akunda JK, Flye-Blakemore L, Van Bockstaele D, Schlenk RF, Sperr WR, Valent P. Cancer Manag Res. 2011;3:157-75. doi: 10.2147/CMR.S19341. Epub 2011 May 10.
BACKGROUND: Acute myeloid leukemia (AML) is a life-threatening malignancy with limited treatment options in chemotherapy-refractory patients. A first-in-human dose study was designed to investigate a safe and biologically effective dose range for LY2457546, a novel multikinase inhibitor, in patients with relapsed AML.
2.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.
Burkholder TP1, Clayton JR, Rempala ME, Henry JR, Knobeloch JM, Mendel D, McLean JA, Hao Y, Barda DA, Considine EL, Uhlik MT, Chen Y, Ma L, Bloem LJ, Akunda JK, McCann DJ, Sanchez-Felix M, Clawson DK, Lahn MM, Starling JJ. Invest New Drugs. 2012 Jun;30(3):936-49. doi: 10.1007/s10637-011-9640-6. Epub 2011 Mar 1.
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.