Modification of a promiscuous inhibitor shifts the inhibition from [gamma]-secretase to FLT-3

Modification of a promiscuous inhibitor shifts the inhibition from [gamma]-secretase to FLT-3

The inhibition of FLT-3 activity is an interesting target for the treatment of acute myeloid leukemia (AML). The serendipitous identification of FLT-3 inhibitors from a CK1/[gamma]-secretase programme provided compounds with dual inhibitory activity. We analyzed the structure-activity relationship o...

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2012-12, Vol.22 (24), p.7634-7640
Hauptverfasser: Amombo, Ghislaine Marlyse Okala, Kramer, Thomas, Lo Monte, Fabio, Goering, Stefan, Fach, Matthias, Smith, Steven, Kolb, Stephanie, Schubenel, Robert, Baumann, Karlheinz, Schmidt, Boris
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Sprache:eng
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Zusammenfassung:The inhibition of FLT-3 activity is an interesting target for the treatment of acute myeloid leukemia (AML). The serendipitous identification of FLT-3 inhibitors from a CK1/[gamma]-secretase programme provided compounds with dual inhibitory activity. We analyzed the structure-activity relationship of these inhibitors and derivatized them to arrive at compounds with reduced impact on [gamma]-secretase activity and enhanced FLT-3 inhibition.
ISSN:0960-894X
DOI:10.1016/j.bmcl.2012.10.016