Prexasertib, also known as LY2606368, is a potent and selective Chk1/Chk2 inhibitor. Prexasertib increases the effectiveness of conventional therapy in B-/T- cell progenitor acute lymphoblastic leukemia. LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms. Treatment of cells with LY2606368 results in the rapid appearance of TUNEL and pH2AX-positive double-stranded DNA breaks in the S-phase cell population.
Prexasertib (LY2606368) is distinguished as a highly selective and ATP-competitive second-generation inhibitor of checkpoint kinase 1 (CHK1), possessing a Ki value of 0.9 nM and an IC50 of less than 1 nM. Its ability to inhibit CHK1 with such potency underlines its mechanism of action, which involves causing double-stranded DNA breaks and replication catastrophe, leading to apoptosis. Beyond CHK1, Prexasertib exhibits inhibition against CHK2 (IC50=8 nM) and RSK1 (IC50=9 nM), demonstrating its broad spectrum of action against other kinases involved in cell cycle regulation and tumor growth[1].[2].
体内研究
In vivo, Prexasertib demonstrates significant anti-tumor efficacy in tumor xenograft models, with dosing regimens leading to growth inhibition. Specifically, when administered subcutaneously at doses ranging from 1-10 mg/kg twice daily for three days with rest periods, it effectively inhibits tumor growth.
Additionally, a dose of 15 mg/kg results in CHK1 inhibition in the blood and increased phosphorylation of H2AX (S139) and RPA2 (S4/S8), markers associated with DNA damage and stress responses[1].
体外研究
Additionally, Prexasertib shows inhibition against a range of other kinases, including MELK (IC50=38 nM), SIK (IC50=42 nM), BRSK2 (IC50=48 nM), and ARK5 (IC50=64 nM), indicating its multi-targeted approach in cancer therapy. It has been noted that the efficacy of LY2606368 in causing DNA damage is dependent on the presence of CDC25A and CDK2, key regulators of cell cycle progression[1].
In cellular assays, Prexasertib has demonstrated significant impact on DNA integrity and cell cycle dynamics. For instance, treatment with Prexasertib results in DNA damage during the S-phase in HeLa cells and inhibits CHK1 and CHK2 autophosphorylation in HT-29 cells, affecting the cells' ability to respond to DNA damage and replication stress[1].
Furthermore, at a concentration of 4 nM for 24 h, it induces a notable shift in cell-cycle populations from G1 and G2-M to S-phase in U-2 OS cells, coupled with the induction of H2AX phosphorylation, a marker of DNA damage[1].
Prexasertib's action extends to causing chromosomal fragmentation in HeLa cells and inducing replication stress, as evidenced by the depletion of available RPA2 for binding to DNA. These mechanisms collectively contribute to its potent anti-tumor activity, highlighting its therapeutic potential[1].
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