title: 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.
authors.affiliation: Discovery Chemistry Research and Technology, Eli Lilly and Company, Indianapolis, IN, USA. tpb@lilly.com
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Burkholder
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Clayton
authors.forename: Mark E
authors.initials: ME
authors.lastname: Rempala
authors.forename: James R
authors.initials: JR
authors.lastname: Henry
authors.forename: John M
authors.initials: JM
authors.lastname: Knobeloch
authors.forename: David
authors.initials: D
authors.lastname: Mendel
authors.forename: Johnathan A
authors.initials: JA
authors.lastname: McLean
authors.forename: Yan
authors.initials: Y
authors.lastname: Hao
authors.forename: David A
authors.initials: DA
authors.lastname: Barda
authors.forename: Eileen L
authors.initials: EL
authors.lastname: Considine
authors.forename: Mark T
authors.initials: MT
authors.lastname: Uhlik
authors.forename: Yuefeng
authors.initials: Y
authors.lastname: Chen
authors.forename: Liandong
authors.initials: L
authors.lastname: Ma
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Bloem
authors.forename: Jacqueline K
authors.initials: JK
authors.lastname: Akunda
authors.forename: Denis J
authors.initials: DJ
authors.lastname: McCann
authors.forename: Manuel
authors.initials: M
authors.lastname: Sanchez-Felix
authors.forename: David K
authors.initials: DK
authors.lastname: Clawson
authors.forename: Michael M
authors.initials: MM
authors.lastname: Lahn
authors.forename: James J
authors.initials: JJ
authors.lastname: Starling
mesh_terms: D000083:Acetanilides / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
chemical_list: D000083:Acetanilides; D020533:Angiogenesis Inhibitors; C574988:LY2457546; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3