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].
Prexasertib Mesylate Hydrate 动物研究
Animal study
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].
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