CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML)

  • Cancer Cell. 2002 Jun;1(5):421-32. doi: 10.1016/s1535-6108(02)00070-3.
Louise M Kelly  1 ,  Jin-Chen Yu ,  Christina L Boulton ,  Mutiah Apatira ,  Jason Li ,  Carol M Sullivan ,  Ifor Williams ,  Sonia M Amaral ,  David P Curley ,  Nicole Duclos ,  Donna Neuberg ,  Robert M Scarborough ,  Anjali Pandey ,  Stanley Hollenbach ,  Keith Abe ,  Nathalie A Lokker ,  D Gary Gilliland ,  Neill A Giese
Affiliations
  • 1. Division of Hematology/Oncology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
PMID: 12124172 DOI: 10.1016/s1535-6108(02)00070-3
Abstract

Up to 30% of acute myelogenous leukemia (AML) patients harbor an activating internal tandem duplication (ITD) within the juxtamembrane domain of the FLT3 receptor, suggesting that it may be a target for kinase inhibitor therapy. For this purpose we have developed CT53518, a potent antagonist that inhibits FLT3, platelet-derived growth factor receptor (PDGFR), and c-Kit (IC(50) approximately 200 nM), while other tyrosine or serine/threonine Kinases were not significantly inhibited. In Ba/F3 cells expressing different FLT3-ITD mutants, CT53518 inhibited IL-3-independent cell growth and FLT3-ITD autophosphorylation with an IC(50) of 10-100 nM. In human FLT3-ITD-positive AML cell lines, CT53518 induced Apoptosis and inhibited FLT3-ITD phosphorylation, cellular proliferation, and signaling through the MAP kinase and PI3 kinase pathways. Therapeutic efficacy of CT53518 was demonstrated both in a nude mouse model and in a murine bone marrow transplant model of FLT3-ITD-induced disease.

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