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Modification of a promiscuous inhibitor shifts the inhibition from Î³-secretase to FLT-3.

Amombo, Ghislaine Marlyse Okala; Kramer, Thomas; Lo Monte, Fabio; Göring, Stefan; Fach, Matthias; Smith, Steven; Kolb, Stephanie; Schubenel, Robert; Baumann, Karlheinz; Schmidt, Boris.

Bioorg Med Chem Lett ; 22(24): 7634-40, 2012 Dec 15.

Article in English | MEDLINE | ID: mdl-23107479

ABSTRACT

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/Î³-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 Î³-secretase activity and enhanced FLT-3 inhibition.

Subject(s)

Amyloid Precursor Protein Secretases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Amyloid Precursor Protein Secretases/metabolism , Animals , Dose-Response Relationship, Drug , Embryo, Nonmammalian/drug effects , Enzyme Inhibitors/chemical synthesis , Humans , Molecular Structure , Phenotype , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/metabolism , Structure-Activity Relationship , Substrate Specificity , Zebrafish/embryology , fms-Like Tyrosine Kinase 3/metabolism

ABSTRACT

Subject(s)

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