One of the intracellular signaling tyrosine kinase receptor, FLT3 (fms-related tyrosine kinase 3/Flk2/Stk-2), is recognized as an important factor in leukemogenesis and is responsible for chemosensitivity in acute myelogenous leukemia (AML). Approximately 30% of AML patients harbor an activating internal tandem duplication (ITD) of the FLT3 receptor, are associated with poor prognosis, suggesting that it may be a target for kinase inhibitor therapy. For this purpose, we used molecular and cellular level kinase panel assay system for fast screening the anti-tumor activities of BEL-K series drugs which constructed by rationale/computer-assisted drug design and virtual screening approaches. We have developed K01109, a potent antagonist that inhibits FLT3, c-Kit and VEGFR-2. In 32D cells expressing different FLT3-ITD mutants, K01109 inhibited IL-3-independent cell growth and FLT3-ITD autophosphorylation. In human FLT3-ITD-positive AML cell lines, K01109 inhibited FLT3-ITD phosphorylation, cellular proliferation, and signaling through the STAT-5, and ERKs Pathways. Therapeutic efficacy of K01109 was demonstrated both in a nude mouse model and in a murine bone marrow transplant model of FLT3-ITD-induced disease.
Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-219.
100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO