WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 205925
Description: LY2457546 is a potent and orally bioavailable inhibitor of multiple receptor tyrosine kinases involved in angiogenic and tumorigenic signalling. LY2457546 demonstrates potent activity against targets that include VEGFR2 (KDR), PDGFRβ, FLT-3, Tie-2 and members of the Eph family of receptors. 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 models. Additionally, LY2457546 caused complete regression of well-established tumors in an acute myelogenous leukemia (AML) FLT3-ITD mutant xenograft tumor model. 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. (source: Invest New Drugs. 2012 Jun;30(3):936-49 )
MedKoo Cat#: 205925
Chemical Formula: C28H20F4N4O
Exact Mass: 504.15732
Molecular Weight: 504.48
Elemental Analysis: C, 66.66; H, 4.00; F, 15.06; N, 11.11; O, 3.17
Synonym: LY2457546; LY 2457546; LY-2457546
IUPAC/Chemical Name: 2-(2-fluoro-4-(7-(2-methylpyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)phenyl)-N-(3-(trifluoromethyl)phenyl)acetamide
InChi Key: HTQYWLPDWPCWTF-UHFFFAOYSA-N
InChi Code: InChI=1S/C28H20F4N4O/c1-17-11-18(7-9-33-17)19-8-10-36-25(16-34-26(36)13-19)21-6-5-20(24(29)12-21)14-27(37)35-23-4-2-3-22(15-23)28(30,31)32/h2-13,15-16H,14H2,1H3,(H,35,37)
SMILES Code: O=C(NC1=CC=CC(C(F)(F)F)=C1)CC2=CC=C(C3=CN=C4C=C(C5=CC(C)=NC=C5)C=CN43)C=C2F
Interim clinical trial results: Five patients were treated at the starting and predicted minimal biologically effective dose of 50 mg/day. The most commonly observed adverse events were febrile neutropenia, epistaxis, petechiae, and headache. The majority of adverse events (81%) were Grade 1 or 2. One patient had generalized muscle weakness (Grade 3), which was deemed to be a dose-limiting toxicity. Notably, the pharmacokinetic profile of LY2457546 showed virtually no elimination of LY2457546 within 24 hours, and thus prevented further dose escalation. No significant DDI were observed. Ex vivo flow cytometry studies showed downregulation of the phosphoproteins, pcKIT, pFLT3, and pS6, in AML blasts after LY2457546 administration. No medically relevant responses were observed in the five treated patients. CONCLUSION: No biologically effective dose could be established for LY2457546 in chemotherapy-resistant AML patients. Lack of drug clearance prevented safe dose escalation, and the study was terminated early. Future efforts should be made to develop derivatives with a more favorable pharmacokinetic profile. (source: Cancer Manag Res. 2011;3:157-75. doi: 10.2147/CMR.S19341. Epub 2011 May 10.)
1: Wacheck V, Lahn M, Dickinson G, FÃ¼reder W, Meyer R, Herndlhofer S, FÃ¼reder T, Dorfner G, Pillay S, AndrÃ© V, Burkholder TP, Akunda JK, Flye-Blakemore L, Van Bockstaele D, Schlenk RF, Sperr WR, Valent P. Dose study of the multikinase inhibitor, LY2457546, in patients with relapsed acute myeloid leukemia to assess safety, pharmacokinetics, and pharmacodynamics. Cancer Manag Res. 2011;3:157-75. doi: 10.2147/CMR.S19341. Epub 2011 May 10. PubMed PMID: 21625399; PubMed Central PMCID: PMC3101112.
2: 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. 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. Invest New Drugs. 2012 Jun;30(3):936-49. doi: 10.1007/s10637-011-9640-6. Epub 2011 Mar 1. Erratum in: Invest New Drugs. 2012 Jun;30(3):1270-1. PubMed PMID: 21360050.