XL228

XL228 is a multi-targeted tyrosine kinase inhibitor with IC₅₀s of 5, 3.1, 1.6, 6.1, 2 nM for Bcr-Abl, Aurora A, IGF-1R, Src and Lyn, respectively. IC50 & Target: IC50:5 nM (Bcr-Abl), 3.1 nM (Aurora A), 1.6 nM (IGF-1R), 6.1 nM (Src), 2 nM (Lyn)^[1] In Vitro: XL228 shows a broad pattern of protein kinase inhibition, including the tyrosine kinases IGF1R, SRC, ABL, FGFR1-3, and ALK and the serine/threonine kinases Aurora A and Aurora B. A panel of kinase inhibitors including XL228 is profiled against a series of cancer cell lines with known alterations in major signaling pathways. Approximately 30% of the lines demonstrate XL228 IC₅₀ values of <100nM in viability assays, including many lines with characterized ALK or FGFR mutations or amplifications. XL228 eliminates the phosphorylation of Aurora A and B at concentrations above 10 nM. Short-term treatment of HeLa cells leads to disruption of mitotic spindle formation, with the majority of mitotic cells exhibiting a unipolar spindle and disorganized chromosomes^[2]. It displays low nanomolar biochemical activity against wild type Abl kinase (K_i=5 nM), as well as the T315I form of Abl resistant to imatinib and dasatinib (K_i=1.4 nM). XL228 inhibits phosphorylation of BCR-ABL and its substrate STAT5 in K562 cells in vitro with IC₅₀s of 33 and 43 nM, respectively^[3]. In Vivo: Single-dose pharmacodynamics studies demonstrate a potent effect of XL228 on BCR-ABL signaling in K562 xenograft tumors. Phosphorylation of BCR-ABL is decreased by 50% at XL228 plasma concentrations of 3.5 μM; a similar decrease in phospho-STAT5 occurred at 0.8 μM plasma concentration^[3].