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.


: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.


Invest New Drugs


Burkholder TP,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




Has Abstract


2012-06-01 00:00:00












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    authors: Sangeetha N,Aranganathan S,Nalini N

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    authors: Shepard DR,Cooney MM,Elson P,Bukowski RM,Dreicer R,Rini BI,Garcia JA

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    authors: Zhang J,Zhou J,Ren X,Diao Y,Li H,Jiang H,Ding K,Pei D

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  • Gilteritinib, a FLT3/AXL inhibitor, shows antileukemic activity in mouse models of FLT3 mutated acute myeloid leukemia.

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    authors: Mori M,Kaneko N,Ueno Y,Yamada M,Tanaka R,Saito R,Shimada I,Mori K,Kuromitsu S

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  • Effect of ketoconazole on the pharmacokinetics of axitinib in healthy volunteers.

    abstract:OBJECTIVE:Axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, is metabolized primarily by cytochrome P450 (CYP) 3A with minor contributions from CYP1A2, CYP2C19, and glucuronidation. Co-administration with CYP inhibitors may increase systemic expos...

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    pub_type: 杂志文章,随机对照试验


    authors: Pithavala YK,Tong W,Mount J,Rahavendran SV,Garrett M,Hee B,Selaru P,Sarapa N,Klamerus KJ

    更新日期:2012-02-01 00:00:00

  • Alterations in human circulating and bone marrow mononuclear cell polyamine levels in hematologic malignancies as a consequence of difluoromethylornithine administration.

    abstract::The effect of administering increasing intravenous doses of difluoromethylornithine on human tumor cell polyamine levels was determined in patients with hematologic malignancies. Difluoromethylornithine from 5.5. to 64 gm/m2 per day was administered to nine patients with refractory acute leukemia or multiple myeloma. ...

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    pub_type: 临床试验,杂志文章


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    pub_type: 杂志文章


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    pub_type: 杂志文章


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    authors: Bradley EC,Issell BF,Hellman R

    更新日期:1984-01-01 00:00:00

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    pub_type: 杂志文章


    authors: Maddox AM,Keating MJ,Freireich EJ,Haddox MK

    更新日期:1989-07-01 00:00:00

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    journal_title:Investigational new drugs

    pub_type: 杂志文章


    authors: Knight WA 3rd,Goodman P,Taylor SA,Macdonald JS,Coltman CA Jr,Constanzi JJ,Baker LH

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    journal_title:Investigational new drugs

    pub_type: 杂志文章,评审


    authors: LeMaistre CF,Knight WA 3rd

    更新日期:1983-01-01 00:00:00

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    journal_title:Investigational new drugs

    pub_type: 杂志文章


    authors: Whittle SB,Patel K,Zhang L,Woodfield SE,Du M,Smith V,Zage PE

    更新日期:2016-12-01 00:00:00

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    journal_title:Investigational new drugs

    pub_type: 临床试验,杂志文章


    authors: Pratt CB,Bowman LC,Marina N,Pappo A,Avery L,Luo X,Meyer WH

    更新日期:1995-01-01 00:00:00

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    journal_title:Investigational new drugs

    pub_type: 杂志文章


    authors: Wilkinson GP,Taylor JP,Shnyder S,Cooper P,Howard PW,Thurston DE,Jenkins TC,Loadman PM

    更新日期:2004-08-01 00:00:00