发明名称 |
APOPTIN INDUCES INHIBITION OF BCR-ABL KINASE IN CML CELLS |
摘要 |
<p>The non-receptor tyrosine kinase activity of fusion gene Bcr-Abl derived oncoproteins is the key factors responsible for development and progress of Philadelphia positive (Ph+) Chronic Myeloid Leukemia (CML) and Ph+ Acute Lymphoblastic Leukemia (ALL). In the search for a peptide-based inhibitor of Bcr- Abl tyrosine kinase, here we investigated a naturally occurring molecule called Apoptin. 'Apoptin1 is a 14 kDa viral protein (chicken anemia virus protein-3, CAV- VP3) and known to induce apoptosis in a wide range of transformed but not in primary cells. During the initial phase of our study an array-based analysis demonstrated that Apoptin interacts with the SH3 domain of AbI. We further investigated the role of Apoptin on Bcr-Abl. High stringent pul!-down and co- immunoprecipitation assays revealed that Apoptin strongly interacts with the fusion protein Bcr-Abl (p210). We also identified Apoptin's ability to significantly inhibit Bcr-Abl kinase and presumably indirectly a series of downstream targets (e.g. CrkL, STATS, c-Myc, etc.). In comparison studies, using lmatinib® we discovered that apoptin has a significant killing efficacy on human and mouse CML celi lines expressing Bcr-Abl. We postulated, the interacting segment of the Apoptin molecule acts as an adaptor and negatively regulates the Bcr-Abl kinase. The obtained data provides foundation for the development of peptide based tyrosine kinase inhibitors as new anti-cancer agents.</p> |
申请公布号 |
WO2009055907(A1) |
申请公布日期 |
2009.05.07 |
申请号 |
WO2008CA01889 |
申请日期 |
2008.10.31 |
申请人 |
UNIVERSITY OF MANITOBA;PANIGRAHI, SOUMYA;LOS, MAREK |
发明人 |
PANIGRAHI, SOUMYA;LOS, MAREK |
分类号 |
A61K38/16;A61K47/48;A61P35/02;C07K14/01;C12Q1/48;G01N33/68 |
主分类号 |
A61K38/16 |
代理机构 |
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代理人 |
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主权项 |
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地址 |
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