898280-07-4

898280-07-4 structure

Name: XL228
Chemical Name: 4-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-2-N-[(3-propan-2-yl-1,2-oxazol-5-yl)methyl]pyrimidine-2,4-diamine
CAS Number: 898280-07-4
Molecular Formula: C₂₂H₃₁N₉O
Molecular Weight: 437.541
Catalog: Signaling Pathways Protein Tyrosine Kinase/RTK Bcr-Abl
Create Date: 2016-10-24 03:00:47
Modify Date: 2024-01-11 09:18:44
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.

Name	4-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-2-N-[(3-propan-2-yl-1,2-oxazol-5-yl)methyl]pyrimidine-2,4-diamine
Synonyms	xl-228 unii-33m2xsk003 2,4-Pyrimidinediamine, N-(5-cyclopropyl-1H-pyrazol-3-yl)-N-[[3-(1-methylethyl)-5-isoxazolyl]methyl]-6-(4-methyl-1-piperazinyl)- N-(5-Cyclopropyl-1H-pyrazol-3-yl)-N-[(3-isopropyl-1,2-oxazol-5-yl)methyl]-6-(4-methyl-1-piperazinyl)-2,4-pyrimidinediamine XL228

Description	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.
Related Catalog	Signaling Pathways >> Protein Tyrosine Kinase/RTK >> Bcr-Abl Signaling Pathways >> Protein Tyrosine Kinase/RTK >> IGF-1R Signaling Pathways >> Protein Tyrosine Kinase/RTK >> Src Research Areas >> Cancer
Target	Aurora A:3.1 nM (IC50) IGF-1R:1.6 nM (IC50)
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 (Ki=5 nM), as well as the T315I form of Abl resistant to imatinib and dasatinib (Ki=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].
References	[1]. Cortes J, et al. Preliminary Clinical Activity in a Phase I Trial of the BCR-ABL/IGF- 1R/Aurora Kinase Inhibitor XL228 in Patients with Ph++ Leukemias with Either Failure to Multiple TKI Therapies or with T315I Mutation. Blood 2008 112:3232 [2]. Douglas O, et al. Abstract C192: Characterization of the target profile of XL228, a multi‐targeted protein kinase inhibitor in phase 1 clinical development. Mol Cancer Ther 2009;8(12 Suppl):C192. [3]. Shah N, et al. Targeting Drug-Resistant CML and Ph+-ALL with the Spectrum Selective Protein Kinase Inhibitor XL228. Blood 2007 110:474;

Density	1.3±0.1 g/cm3
Boiling Point	715.7±70.0 °C at 760 mmHg
Molecular Formula	C₂₂H₃₁N₉O
Molecular Weight	437.541
Flash Point	386.6±35.7 °C
Exact Mass	437.265167
PSA	117.49000
LogP	1.35
Vapour Pressure	0.0±2.3 mmHg at 25°C
Index of Refraction	1.669
Storage condition	2-8℃

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