Tyrosine Kinase Receptor Inhibitors Rtki

These agents inhibit signaling pathways activated by ligand binding to vascular endothelial growth factor (VEGF) receptors (VEGFRs) and other type III receptors, including c-kit, Flt-3, platelet-derived growth factor receptor p (PDGFRp), and basic fibroblast growth factor (bFGF). By selectively mimicking ATP, these molecules impair autophosphorylation of the tyrosine kinase domain of the receptor (RTK). SU5416 is a small, lipophilic, highly protein-bound, synthetic RTK inhibitor of VEGFR-2. SU5416 binds to the ATP domain on the kinase, affecting VEGF-dependent cell proliferation. In a human colon cancer xenograft model, this molecule inhibits tumor metastases, microvessel formation, and proliferation. Like other

RTKIs, SU5416 also targets c-kit (expressed in AML blasts in 60-80% patients) and Flt-3 (mutated in about 30% of AML patients), prompting clinical studies for the treatment of AML and MDS.

A multicenter phase II study was conducted in patients with refractory AML (n = 33) or MDS (n = 22), all of whom received 145 mg/m2 of SU5416 twice weekly i.v. for a median of 9 weeks.21 Eleven patients could not complete 4 weeks of therapy (mainly due to disease progression). Three patients had a partial response and one had a hematologic response. Phase I and II studies are ongoing with SU11248 and two other RTKIs, PTK/ZK and AG13736, alone or in combination with chemotherapy.22-24

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