Arzneimittelforschung 2011; 61(4): 252-259
DOI: 10.1055/s-0031-1296196
Antibiotics · Antimycotics · Antiparasitics · Antiviral Drugs · Chemotherapeutics · Cytostatics
Editio Cantor Verlag Aulendorf (Germany)

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

Fatih Uckun
1   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, USA
2   Developmental Therapeutics Program, Childrens Center for Cancer and Blood Diseases, Childrens Hospital Los Angeles MS#57, Los Angeles, CA, USA
3   Developmental Therapeutics Program, USC Comprehensive Norris Cancer Center, Los Angeles, CA, USA
,
Ilker Dibirdik
2   Developmental Therapeutics Program, Childrens Center for Cancer and Blood Diseases, Childrens Hospital Los Angeles MS#57, Los Angeles, CA, USA
,
Aniee Sarkissian
2   Developmental Therapeutics Program, Childrens Center for Cancer and Blood Diseases, Childrens Hospital Los Angeles MS#57, Los Angeles, CA, USA
,
Sanjive Qazi
4   Department of Biology and Bioinformatics Program, Gustavus Adolphus College, St. Peter, MN, USA
› Author Affiliations
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Publication History

Publication Date:
27 November 2011 (online)

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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 Pololike 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. A11 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.