Checkpoint kinase 1 (Chk1) is a conserved protein kinase that is critical to the Cell cycle checkpoint during DNA damage response (DDR). Specifically, CHK1 is the regulatory factor for G2/M checkpoints. Besides, it plays an important role in DNA replication, Mitosis progression, DNA repair, and overall cell cycle regulation. Moreover, CHK1 plays a role in various cellular processes, most notably in the cell cycle and DNA damage response. ATR (a protein kinase activated by DNA damage or replication arrest) is a regulatory factor of Chk1. Furthermore, the spatiotemporal regulation of Chk1 is crucial in DDR and normal cell cycle processes. In the undisturbed cell cycle, Chk1 regulates DNA replication, G2/M transformation or Mitosis entry, and Mitosis completion in the S phase.
Meanwhile, the cell cycle includes an orderly transition from G1, S, and G2 to the M phase, leading to cell division and proliferation. During DNA damage, Chk1 is activated through phosphorylation of its C-terminal domain. Nonetheless, CHK1 deficiency can lead to severe proliferation defects, death of embryonic stem (ES) cells, and lethal implantation of surrounding embryos in mice. Today, we will introduce a selective CHK1 inhibitor, MU380.
MU380 is a CHK1 Inhibitor for the Research of Chronic Lymphocytic Leukemia.
Above all, MU380 is a potent and selective CHK1 inhibitor that induces apoptosis and has anticancer activity. Importantly, MU380 with 100 nM for 24 h potently inhibits CHK1 kinase and sensitizes lymphoid tumor cells to gemcitabine.
Next in importance, MU380 can significantly affect the cell cycle profile and induce the death of dividing and non-dividing primary chronic lymphocytic leukemia lymphocytes. Particularly, MU380 showed accumulation in the S phase as well as a reduction in the G2/M phase. Obviously, MU380 greatly reduced the rate of DNA synthesis and marked induction of apoptosis (PARP protein cleavage).
Once again, MU380 with 20 mg/kg every three days from day 14 to day 28 can effectively inhibit tumor growth in NOD-scid IL2Rγnull mice with tumors. Additionally, MU380 significantly inhibits the growth of tumors and gradually reduces their volume, with an average reduction of about 61%.
All in all, MU380 is a potent and selective CHK1 inhibitor for the research of chronic lymphocytic leukemia.
References:
[1] Miroslav Boudny, et al. Haematologica. 2019 Dec;104(12):2443-2455.