AFP-464 - CAS 468719-52-0
Catalog number: 468719-52-0
Category: Inhibitor
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Molecular Formula:
C23H27F3N4O6S
Molecular Weight:
448.4462
COA:
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Description:
AFP-464 is a synthetic lysyl prodrug of the amino-substituted flavone derivate aminoflavone with antiproliferative and antineoplastic activities. AFP464 is rapidly converted to aminoflavone in plasma. Aminoflavone activates the aryl hydrocarbon receptor (AhR) signaling pathway leading to an increase in cytochrome P450 1A1 (CYP1A1) and cytochrome P450 1A2 (CYP1A2) expression and, to a lesser extent, an increase in cytochrome P450 1B1 (CYP1B1) expression.
Synonyms:
AFP464.
MSDS:
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InChIKey:
MJVICFBYAVBBOA-ZOWNYOTGSA-N
InChI:
InChI=1S/C22H23F3N4O3.CH4O3S/c1-10-18(24)20(28)17-15(30)9-16(32-21(17)19(10)25)11-5-6-14(12(23)8-11)29-22(31)13(27)4-2-3-7-26;1-5(2,3)4/h5-6,8-9,13H,2-4,7,26-28H2,1H3,(H,29,31);1H3,(H,2,3,4)/t13-;/m0./s1
Canonical SMILES:
CC1=C(C(=C2C(=O)C=C(OC2=C1F)C3=CC(=C(C=C3)NC(=O)C(CCCCN)N)F)N)F.CS(=O)(=O)O
Current Developer:
Tigris Pharmaceuticals, Inc/ Kirax Corp.
1.Aminoflavone, a ligand of the aryl hydrocarbon receptor, inhibits HIF-1alpha expression in an AhR-independent fashion.
Terzuoli E;Puppo M;Rapisarda A;Uranchimeg B;Cao L;Burger AM;Ziche M;Melillo G Cancer Res. 2010 Sep 1;70(17):6837-48. doi: 10.1158/0008-5472.CAN-10-1075. Epub 2010 Aug 24.
Aminoflavone (AF), the active component of a novel anticancer agent (AFP464) in phase I clinical trials, is a ligand of the aryl hydrocarbon receptor (AhR). AhR dimerizes with HIF-1beta/AhR, which is shared with HIF-1alpha, a transcription factor critical for the response of cells to oxygen deprivation. To address whether pharmacologic activation of the AhR pathway might be a potential mechanism for inhibition of HIF-1, we tested the effects of AF on HIF-1 expression. AF inhibited HIF-1alpha transcriptional activity and protein accumulation in MCF-7 cells. However, inhibition of HIF-1alpha by AF was independent from a functional AhR pathway. Indeed, AF inhibited HIF-1alpha expression in Ah(R100) cells, in which the AhR pathway is functionally impaired, yet did not induce cytotoxicity, providing evidence that these effects are mediated by distinct signaling pathways. Moreover, AF was inactive in MDA-MB-231 cells, yet inhibited HIF-1alpha in MDA-MB-231 cells transfected with the SULT1A1 gene. AF inhibited HIF-1alpha mRNA expression by approximately 50%. Notably, actinomycin-D completely abrogated the ability of AF to downregulate HIF-1alpha mRNA, indicating that active transcription was required for the inhibition of HIF-1alpha expression.
2.Cytochrome P450 1A1-mediated anticancer drug discovery: in silico findings.
Nandekar PP;Sangamwar AT Expert Opin Drug Discov. 2012 Sep;7(9):771-89. doi: 10.1517/17460441.2012.698260. Epub 2012 Jun 21.
INTRODUCTION: ;Target-specific drugs may offer fewer side/adverse effects in comparison with other anticancer agents and thus save normal healthy cells to a greater extent. The selective overexpression of cytochrome P450 1A1 (CYP1A1) in tumor cells induces the metabolism of benzothiazole and aminoflavone compounds to their reactive species, which are responsible for DNA adduct formation and cell death. This review encompasses the novelty of CYP1A1 as an anticancer drug target and explores the possible in silico strategies that would be applicable in the discovery and development of future antitumor compounds.;AREAS COVERED: ;This review highlights the various ligand-based and target-based in silico methodologies that were efficiently used in exploration of CYP1A1 as a novel antitumor target. These methodologies include electronic structure analysis, CoMFA studies, homology modeling, molecular docking, molecular dynamics analysis, pharmacophore mapping and quantitative structure activity relationship (QSAR) studies. It also focuses on the various approaches used in the development of the lysyl amide prodrug of 5F-203 (NSC710305) and dimethanesulfonate salt of 5-aminoflavone (NSC710464) as clinical candidates from their less potent analogues.
3.Synergistic interactions between aminoflavone, paclitaxel and camptothecin in human breast cancer cells.
Reinicke KE;Kuffel MJ;Goetz MP;Ames MM Cancer Chemother Pharmacol. 2010 Aug;66(3):575-83. doi: 10.1007/s00280-009-1198-z. Epub 2009 Dec 11.
PURPOSE: ;Aminoflavone is a unique DNA damaging agent currently undergoing phase I evaluation in a prodrug form (AFP464). In anticipation of combination regimens, interactions between aminoflavone and several anticancer drugs were investigated in MCF-7 breast cancer cells to determine whether synergistic cancer cell killing effects were observed.;METHODS: ;Colony formation assays were performed to assess the effect of combining aminoflavone with a variety of anticancer drugs. Changes in initial uptake, retention or efflux of aminoflavone and the second agent were compared to the behavior of drugs alone. Key features required for aminoflavone activity in cell culture models were also explored, focusing on the obligatory induction of CYP1A1/1A2 and binding of reactive aminoflavone metabolites to tumor cell total macromolecules and DNA.;RESULTS: ;Aminoflavone was synergistic when co-incubated with paclitaxel, camptothecin or SN38. Uptake of neither aminoflavone nor any of the other three compounds was altered in combination incubations. Paclitaxel did not inhibit DNA binding of aminoflavone metabolites, while camptothecin did. Aminoflavone-induced CYP1A1 induction was observed in the presence of camptothecin or paclitaxel.
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CAS 468719-52-0 AFP-464

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