Novel CHK1 inhibitor MU380 exhibits significant single-agent activity in TP53-mutated chronic lymphocytic leukemia cells
Novel CHK1 inhibitor MU380 exhibits significant single-agent activity in TP53-mutated chronic lymphocytic leukemia cells
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DOI：
10.3324/haematol.2018.203430
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发表时间：
2019-12-01
期刊：
影响因子：
10.1
通讯作者：
Trbusek, Martin
中科院分区：
文献类型：
--
作者：
Boudny, Miroslav;Zemanova, Jana;Trbusek, Martin
B细胞受体信号传导和BCL 2蛋白的小分子抑制剂的引入显著改善了慢性淋巴细胞白血病的治疗选择然而，一些患者遭受的不良反应要求治疗中止，与TP 53缺陷的情况下，更频繁地经历早期疾病进展。因此，开发替代治疗方法至关重要。在这里，我们报告了MU 380的抗慢性淋巴细胞白血病单药活性的细节，MU 380是我们最近发现的强效，选择性和代谢稳健的检查点激酶1抑制剂。我们还描述了一种新开发的MU 380的对映选择性合成，它允许制备克量的物质。检查点激酶1是主要在S和G（2）/M细胞周期检查点内操作的复制的主要调节剂。最初在白血病和淋巴瘤细胞系中测试，MU 380显著增强吉西他滨（临床上使用的复制应激诱导剂）的功效。此外，MU 380在TP 53野生型和TP 53突变的白血病和淋巴瘤细胞系中表现出显著的单药活性。在慢性淋巴细胞白血病衍生的细胞系MEC-1、MEC-2（均为TP 53-mut）和OSU-CLL（TP 53-wt）中，抑制剂损害细胞周期进程并诱导细胞凋亡。在初级临床样品中，MU 380作为单一药剂使用显著降低未刺激的慢性淋巴细胞白血病细胞以及由抗CD 40/IL-4刺激诱导增殖的细胞的活力。在这两种情况下，在携带p53通路功能障碍（TP 53突变或ATM突变）的样品和TP 53-wt/ATM-wt细胞中的效果是相当的。最后，MU 380在异种移植小鼠模型（免疫缺陷株NOD-scid IL 2 R γ（null））中也表现出显著的体内活性，其中其有效抑制由MEC-1细胞产生的皮下肿瘤的生长。
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. Here we report details of the 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 G(2)/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 IL2R gamma(null)) where it efficiently suppressed growth of subcutaneous tumors generated from MEC-1 cells.