title: In vitro and in vivo chemosensitizing activity of LFM-A13, a dual-function inhibitor of Bruton's tyrosine kinase and polo-like kinases, against human leukemic B-cell precursors.
abstract: The present study documents the chemosensitizing anti-leukemic activity of the leflunomide metabolite (LFM) analog, LFM-A13, a dual-function inhibitor of Bruton's tyrosine kinase (BTK) and Polo-like kinases (PLK), against human leukemic B-cell precursors. The results in 135 xenografted NOD/SCID mice regarding the anti-leukemic activity of GMP-grade LFM-A13, obtained with only 4-days of LFM-A13 therapy at nontoxic dose levels corresponding to 1-20% of its NOAEL (no observable advserse effect level), alone or in combination with the standard chemotherapy drug vincristine, demonstrate the potential of LFM-A13 as a new anti-leukemic drug candidate. All 82 LFM-A13-treated mice, including those receiving a combination of vincristine + LFM-A13 at the highest dose level of LFM-A13, tolerated their treatments well without weight loss, diarrhea, lethargy/ paralysis, other signs of morbidity, or mortality. The present study provides preclinical proof-of-principle for the development of LFM-A13 as a new chemosensitizing and apoptosis-promoting anti-leukemic agent and lends support to the hypothesis that the chemoresistance of relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL) can be overcome by using LFM-A13 in combination with chemotherapy. Also presented are the results of a comprehensive meta-analysis of the overexpression of genes for LFM-A13 targeted kinases and their downstream effector molecules in B-lineage lymphoid malignancies utilizing the Oncomine database.
authors.affiliation: Division of Hematology-Oncology, Department of Pediatrics, Childrens Center for Cancer and Blood Diseases, University of Southern California Keck School of Medicine, Los Angeles, CA 90027-0367, USA. fmuckun@chla.usc.edu
authors.forename: Fatih
authors.initials: F
authors.lastname: Uckun
authors.forename: Ilker
authors.initials: I
authors.lastname: Dibirdik
authors.forename: Aniee
authors.initials: A
authors.lastname: Sarkissian
authors.forename: Sanjive
authors.initials: S
authors.lastname: Qazi
mesh_terms: D000277:Adjuvants, Pharmaceutic / Q000494:pharmacology*; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000577:Amides / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D019070:Cell Lineage; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009570:Nitriles / Q000494:pharmacology*; D054448:Precursor Cells, B-Lymphoid / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013379:Substrate Specificity
chemical_list: D000277:Adjuvants, Pharmaceutic; D000577:Amides; D000970:Antineoplastic Agents; C118451:LFM A13; D009570:Nitriles; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; D017346:Protein Serine-Threonine Kinases