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Chronic Lymphocyic Leukemia
Novel CHK1 inhibitor MU380 exhibits significant single-agent activity in TP53-mutated chronic lymphocytic leukemia cells
Ferrata Storti Foundation
Haematologica 2019 Volume 104(12):2443-2455
Miroslav Boudny,1 Jana Zemanova,1 Prashant Khirsariya,2,3 Marek Borsky,1 Jan Verner,1 Jana Cerna,1 Alexandra Oltova,1 Vaclav Seda,1,4 Marek Mraz,1,4 Josef Jaros,5 Zuzana Jaskova,1 Michaela Spunarova,1 Yvona Brychtova,1 Karel Soucek,3,6,7 Stanislav Drapela,3,6,7 Marie Kasparkova,1 Jiri Mayer,1 Kamil Paruch,2,3 and Martin Trbusek1
1Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University; 2Department of Chemistry, CZ Openscreen, Faculty of Science, Masaryk University; 3Center of Biomolecular and Cellular Engineering, International Clinical Research Center, St. Anne's University Hospital; 4Center of Molecular Medicine, Central European Institute of Technology, Masaryk University; 5Department of Histology and Embryology, Faculty of Medicine, Masaryk University; 6Department of Cytokinetics, Institute of Biophysics CAS, v.v.i. and 7Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
ABSTRACT
Introduction of small-molecule inhibitors of B-cell receptor signaling and BCL2 protein significantly improves therapeutic options in chronic lym- phocytic leukemia. However, some patients suffer from adverse effects mandating treatment discontinuation, and cases with TP53 defects more frequently experience early progression of the disease. Development of alternative therapeutic approaches is, therefore, of critical importance. Here we report details of the anti-chronic lymphocytic leukemia single-agent activity of MU380, our recently identified potent, selective, and metaboli- cally robust inhibitor of checkpoint kinase 1. We also describe a newly developed enantioselective synthesis of MU380, which allows preparation of gram quantities of the substance. Checkpoint kinase 1 is a master regu- lator of replication operating primarily in intra-S and G2/M cell cycle check- points. Initially tested in leukemia and lymphoma cell lines, MU380 signif- icantly potentiated efficacy of gemcitabine, a clinically used inducer of repli- cation stress. Moreover, MU380 manifested substantial single-agent activity in both TP53-wild type and TP53-mutated leukemia and lymphoma cell lines. In chronic lymphocytic leukemia-derived cell lines MEC-1, MEC-2 (both TP53-mut), and OSU-CLL (TP53-wt) the inhibitor impaired cell cycle progression and induced apoptosis. In primary clinical samples, MU380 used as a single-agent noticeably reduced the viability of unstimulated chronic lymphocytic leukemia cells as well as those induced to proliferate by anti-CD40/IL-4 stimuli. In both cases, effects were comparable in sam- ples harboring p53 pathway dysfunction (TP53 mutations or ATM muta- tions) and TP53-wt/ATM-wt cells. Lastly, MU380 also exhibited significant in vivo activity in a xenotransplant mouse model (immunodeficient strain NOD-scid IL2Rgnull) where it efficiently suppressed growth of subcutaneous tumors generated from MEC-1 cells.
Introduction
Significant progress has been achieved in the therapy of chronic lymphocytic leukemia (CLL) with the introduction of small-molecule inhibitors targeting the B-cell receptor (BCR) signaling1,2 and BCL2 protein.3 Drugs like ibrutinib, idelalisib or vene- toclax are currently changing clinical practice in CLL treatment. The most extensive data are related to the BCR inhibitor ibrutinib, and besides many positive aspects revealed also that: (i) the drug possesses a specific toxicity profile enforcing treatment
Correspondence:
MARTIN TRBUSEK
Trbusek.Martin@fnbrno.cz
KAMIL PARUCH
paruch@chemi.muni.cz
Received: July 31, 2018. Accepted: April 5, 2019. Pre-published: April 11, 2019.
doi:10.3324/haematol.2018.203430
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/12/2443
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