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Targeting SYK kinase‐dependent anti‐apoptotic resistance pathway in B‐lineage acute lymphoblastic leukaemia (ALL) cells with a potent SYK inhibitory pentapeptide mimic
Author(s) -
Uckun Fatih M.,
Ek Rauf O.,
Jan ShyiTai,
Chen ChunLin,
Qazi Sanjive
Publication year - 2010
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2010.08106.x
Subject(s) - syk , cancer research , in vivo , apoptosis , pentapeptide repeat , chemotherapy , biology , clonogenic assay , immunology , in vitro , medicine , pharmacology , tyrosine kinase , microbiology and biotechnology , signal transduction , biochemistry , peptide
Summary The present study found that the pentapeptide mimic C‐61, targeting the substrate binding P‐site of SYK tyrosine kinase acted as a potent inducer of apoptosis in chemotherapy‐resistant SYK‐expressing primary leukemic B‐cell precursors taken directly from relapsed B‐precursor leukaemia (BPL) patients (but not SYK‐deficient infant pro‐B leukaemia cells), exhibited favourable pharmacokinetics in mice and non‐human primates, and eradicated in vivo clonogenic leukaemia cells in severe combined immunodeficient mouse xenograft models of chemotherapy‐resistant human BPL at dose levels non‐toxic to mice and non‐human primates. These in vitro and in vivo findings provide proof of principle for effective treatment of chemotherapy‐resistant BPL by targeting SYK‐dependent anti‐apoptotic blast cell survival machinery with a SYK P‐Site inhibitor. Further development of C‐61 may provide the foundation for therapeutic innovation against chemotherapy‐resistant BPL.