| Stereochemistry | ACHIRAL |
| Molecular Formula | C22H31N9O |
| Molecular Weight | 437.5412 |
| Optical Activity | NONE |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
CC(C)C1=NOC(CNC2=NC(=CC(NC3=NNC(=C3)C4CC4)=N2)N5CCN(C)CC5)=C1
InChI
InChIKey=ALKJNCZNEOTEMP-UHFFFAOYSA-N
InChI=1S/C22H31N9O/c1-14(2)17-10-16(32-29-17)13-23-22-25-19(24-20-11-18(27-28-20)15-4-5-15)12-21(26-22)31-8-6-30(3)7-9-31/h10-12,14-15H,4-9,13H2,1-3H3,(H3,23,24,25,26,27,28)
XL-228 is a third generation inhibitor of Abl that shows efficacy in a variety of cell lines, including those exhibiting T315I mutations. XL-228, a tyrosine kinase inhibitor, is involved in binding to and inhibiting the activities of multiple tyrosine kinases, such as the insulin-like growth factor 1 receptor (IGF1R), Src tyrosine kinase, and Bcr-Abl tyrosine kinase. Blockade of these kinases may result in the inhibition of tumor angiogenesis, cell proliferation, and metastasis. XL-228 is a multitargeted protein kinase inhibitor targeting IGF1R, the aurora kinases, IGF-1R, cSrc, BCR/Abl and SRC kinases. XL-228 displays anticancer chemotherapeutic activity and it was in clinical trials as a potential treatment for chronic myelogenous leukemia (CML). On 22 Feb 2011 phase I clinical studies for chronic myeloid leukaemia and cancer in USA were discontinued.
Originator
Approval Year
Doses
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Sample Use Guides
XL-228 is administered as weekly 1-hr IV infusions at the MTD of 6.5 mg/kg. The dose escalation phase is complete, with 41 pts treated with XL-228 at dose levels ranging from 0.45 to 8.0 mg/kg. The dose limiting toxicity was Grade 3 and 4 neutropenia occurring at the 8.0 mg/kg dose level.
Route of Administration:
Intravenous
XL-228(5-100 nM) reduced cell survival by 10-70% in a dose and time dependent manner and inhibited migration and invasion of two tumors with high propensity to metastasize, FaDu and H460. Treatment with 50 and 100 nM XL-228 abolished the ability of H460, A549 and FaDu cells to form colony. At 10 nM, XL-228 significantly increased the radiosensitivity of H460, A549 and FaDu cells by enhancement factors (EF, at the survival fraction of 0.5) of 1.52, 1.31 and 1.67 respectively.
ACTIVE MOIETY
