Modification of a promiscuous inhibitor shifts the inhibition from γ-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/γ-secretase programme provided compounds with dual inhibitory activity. We analyzed the structure–activity relationship of thes...

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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, Göring, Stefan, Fach, Matthias, Smith, Steven, Kolb, Stephanie, Schubenel, Robert, Baumann, Karlheinz, Schmidt, Boris
Format:	Artikel
Sprache:	eng
Schlagworte:	Acute myeloid leukemia Amyloid Precursor Protein Secretases - antagonists & inhibitors Amyloid Precursor Protein Secretases - metabolism Animals Biological and medical sciences Dose-Response Relationship, Drug Embryo, Nonmammalian - drug effects Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology FLT-3 fms-Like Tyrosine Kinase 3 - antagonists & inhibitors fms-Like Tyrosine Kinase 3 - metabolism Humans Kinase inhibitor Medical sciences Molecular Structure Pharmacology. Drug treatments Phenotype Recombinant Proteins - antagonists & inhibitors Recombinant Proteins - metabolism Structure-Activity Relationship Substrate Specificity Zebrafish - embryology γ-Secretase
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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/γ-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 γ-secretase activity and enhanced FLT-3 inhibition.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2012.10.016