title: Nanoscale liposomal formulation of a SYK P-site inhibitor against B-precursor leukemia.
abstract: We report preclinical proof of principle for effective treatment of B-precursor acute lymphoblastic leukemia (ALL) by targeting the spleen tyrosine kinase (SYK)-dependent antiapoptotic blast cell survival machinery with a unique nanoscale pharmaceutical composition. This nanoscale liposomal formulation (NLF) contains the pentapeptide mimic 1,4-Bis (9-O dihydroquinidinyl) phthalazine/hydroquinidine 1,4-phathalazinediyl diether (C61) as the first and only selective inhibitor of the substrate binding P-site of SYK. The C61 NLF exhibited a very favorable pharmacokinetic and safety profile in mice, induced apoptosis in primary B-precursor ALL blast cells taken directly from patients as well as in vivo clonogenic ALL xenograft cells, destroyed the in vivo clonogenic fraction of ALL blast cells, and, at nontoxic dose levels, exhibited potent in vivo antileukemic activity against patient-derived ALL cells in xenograft models of aggressive B-precursor ALL. Our findings establish SYK as an attractive molecular target for therapy of B-precursor ALL. Further development of the C61 NLF may provide the foundation for therapeutic innovation against therapy-refractory B-precursor ALL.
authors.affiliation: Developmental Therapeutics Program, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA. uckun@usc.edu
authors.forename: Fatih M
authors.initials: FM
authors.lastname: Uckun
authors.forename: Sanjive
authors.initials: S
authors.lastname: Qazi
authors.forename: Ingrid
authors.initials: I
authors.lastname: Cely
authors.forename: Kazim
authors.initials: K
authors.lastname: Sahin
authors.forename: Anoush
authors.initials: A
authors.lastname: Shahidzadeh
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Ozercan
authors.forename: Qian
authors.initials: Q
authors.lastname: Yin
authors.forename: Paul
authors.initials: P
authors.lastname: Gaynon
authors.forename: Amanda
authors.initials: A
authors.lastname: Termuhlen
authors.forename: Jianjun
authors.initials: J
authors.lastname: Cheng
authors.forename: Seang
authors.initials: S
authors.lastname: Yiv
mesh_terms: D000818:Animals; D002648:Child; D006801:Humans; D051379:Mice; D017209:Apoptosis / Q000187:drug effects; D004337:Drug Carriers / Q000493:pharmacokinetics / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D008081:Liposomes / Q000493:pharmacokinetics / Q000494:pharmacology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D054118:Nanospheres; D010793:Phthalazines / Q000493:pharmacokinetics / Q000494:pharmacology; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D000072377:Syk Kinase; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D004337:Drug Carriers; D047908:Intracellular Signaling Peptides and Proteins; D008081:Liposomes; D010793:Phthalazines; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606896:SYK protein, human; C000606897:Syk protein, mouse; C000715707:(SYK) inhibitor C61