CHIR-258: A Potent Inhibitor of FLT3 Kinase in Experimental Tumor Xenograft Models of Human Acute Myelogenous Leukemia

Abstract

Purpose: Fms-like tyrosine kinase 3 (FLT3) encodes a receptor tyrosine kinase (RTK) for which activating mutations have been identified in a proportion of acute myelogenous leukemia (AML) patients and associated with poor clinical prognosis. Given the relevance of FLT3 mutations in AML, we investigated the activity of CHIR-258, an orally active, multitargeted small molecule, with potent activity against FLT3 kinase and class III, IV, and V RTKs involved in endothelial and tumor cell proliferation in AML models. Experimental Design: CHIR-258 was tested on two human leukemic cell lines in vitro and in vivo with differing FLT3 mutational status [MV4;11 cells express FLT3 internal tandem duplications (ITD) versus RS4;11 cells with wild-type (WT) FLT3]. Results: Antiproliferative activity of CHIR-258 against MV4;11was f24-fold greater compared with RS4;11, indicating more potent inhibition against cells with constitutively activated FLT3 ITD. Dose-dependent down modulation of receptor phosphorylation and downstream signaling [signal transducer and activator of transcription 5 (STAT5) and extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase] in MV4;11 cells with CHIR-258 confirmed the molecular mechanism of action. Target modulation of phospho-FLT3, phospho-STAT5, and phospho-ERK in MV4;11 tumors was achieved at biologically active doses of CHIR-258. Tumor regressions and eradication of AML cells from the bone marrow were shown in s.c. and bone marrow engraftment leukemic xenograft models. Tumor responses were characterized by decreased cellular proliferation and positive immunohistochemical staining for active caspase-3 and cleaved poly(ADP-ribose) polymerase, suggesting cell death was mediated in part via apoptosis. Conclusions: Our data indicate that CHIR-258 may be an effective therapy in FLT3-associated AML and warrants clinical trials.

Targeting multiple tyrosine kinase receptors with Dovitinib blocks invasion and the interaction between tumor cells and cancer-associated fibroblasts in breast cancer

“…28 Dovitinib has almost equal in vitro inhibitory activity against bFGF and PDFG receptor kinases with IC 50 values of approximately 10 nM. 29 In accordance with the previous preclinical and clinical data, interruption of the PDGF signaling by Dovitinib led to reduced breast cancer cell invasion in our in vitro test model (Figs. 3A and B).…”

The Novel Oral Hsp90 Inhibitor NVP-HSP990 Exhibits Potent and Broad-spectrum Antitumor ActivitiesIn VitroandIn Vivo

“…occurrence of FLT3-ITD mutations in patients with AML, we investigated the activity of NVP-HSP990 given twice weekly at 5 mg/kg and weekly at 15 mg/kg in the MV4;11 xenograft model, which expresses FLT3-ITD. MV4;11 has been shown to be dependent on FLT3-ITD by its sensitivity to selective FLT3 kinase inhibitors (29). Both treatment regimens resulted in significant antitumor efficacy compared with the group receiving the dosing vehicle alone (%T/C of 3% with twice weekly and 5% regressions weekly; P < 0.05; Fig.…”

p90RSK2 is essential for FLT3-ITD– but dispensable for BCR-ABL–induced myeloid leukemia

“…We first targeted FLT3-ITD in these cells by using TKI258 (4-amino-5-fluor-3-[5-(4-metylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one, formerly known as CHIR258), which is an adenosine triphosphate-competitive inhibitor with activities against class III or IV receptor kinases including FGFR, VEGFR, PDGFR, FLT3, and c-kit receptor tyrosine kinase. 41,42 Targeting FLT3-ITD by TKI258 led to markedly reduced S386 phosphorylation levels of RSK2 in these cells ( Figure 1C, supplemental Figure 1B). In addition, inhibition of FLT3-ITD by 2 alternative FLT3 inhibitors, CEP701 and MLN518, also resulted in decreased RSK2 activation (supplemental Figure 2).…”