Targeting SYK kinase-dependent anti-apoptotic resistance pathway in B-lineage acute lymphoblastic leukaemia (ALL) cells with a potent SYK inhibitory pentapeptide mimic.
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.
Uckun
Fatih M
FM
Developmental Therapeutics Program, Institute for Peadiatric Clinical Research, Childrens Hospital Los Angeles, and Department of Pediatrics, University of Southern California, Keck School of Medicine, Los Angeles, CA 90027-0367, USA. fmuckun@chla.usc.edu
Ek
Rauf O
RO
Jan
Shyi-Tai
ST
Chen
Chun-Lin
CL
Qazi
Sanjive
S
D000293:Adolescent; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002648:Child; D004353:Drug Evaluation, Preclinical / Q000379:methods; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010793:Phthalazines / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011802:Quinidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D016019:Survival Analysis; D000072377:Syk Kinase; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
D047908:Intracellular Signaling Peptides and Proteins; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D011802:Quinidine