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Haematologica. 2019 Apr 11. pii: haematol.2018.203430. doi: 10.3324/haematol.2018.203430. [Epub ahead of print]

Novel CHK1 inhibitor MU380 exhibits significant single-agent activity in TP53-mutated chronic lymphocytic leukemia cells.

Author information

1
University Hospital Brno and Faculty of Medicine, Masaryk University.
2
Faculty of Science, Masaryk University.
3
Faculty of Medicine, Masaryk University.
4
Institute of Biophysics, Czech Academy of Sciences.
5
University Hospital Brno and Faculty of Medicine, Masaryk University; trbusek.martin@fnbrno.cz.

Abstract

Introduction of small-molecule inhibitors of B-cell receptor signaling and BCL2 protein significantly improves therapeutic options in chronic lymphocytic 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. Herein, we detail anti-chronic lymphocytic leukemia single-agent activity of MU380, our recently identified potent, selective, and metabolically 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 regulator of replication operating primarily in intra-S and G2/M cell cycle checkpoints. Initially tested in leukemia and lymphoma cell lines, MU380 significantly potentiated efficacy of gemcitabine, a clinically used inducer of replication 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 samples harboring p53 pathway dysfunction (TP53 mutations or ATM mutations) and TP53-wt/ATM-wt cells. Lastly, MU380 also exhibited significant in vivo activity in a xenotransplant mouse model (immunodeficient strain NOD-scid IL2Rγnull) where it efficiently suppressed growth of subcutaneous tumors generated from MEC-1 cells.

KEYWORDS:

ATR; Checkpoint kinase 1 (CHK1); Chronic Lymphocytic Leukemia; MU380; TP53/p53

PMID:
30975914
DOI:
10.3324/haematol.2018.203430
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