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

  • Bioorg Med Chem Lett. 2012 Dec 15;22(24):7634-40. doi: 10.1016/j.bmcl.2012.10.016.
Ghislaine Marlyse Okala Amombo  1 ,  Thomas Kramer ,  Fabio Lo Monte ,  Stefan Göring ,  Matthias Fach ,  Steven Smith ,  Stephanie Kolb ,  Robert Schubenel ,  Karlheinz Baumann ,  Boris Schmidt
Affiliations
  • 1. Clemens Schöpf-Institute of Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Petersenstr. 22, D-64287 Darmstadt, Germany.
PMID: 23107479 DOI: 10.1016/j.bmcl.2012.10.016
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/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.