Prexasertib dihydrochloride (LY2606368 dihydrochloride) is a potent and selective ATP competitive inhibitor of the Chk1 protein kinase, with IC50s of <1 nM and 8 nM for CHK1 and CHK2, respectively, and a Ki of 0.9 nM against purified CHK1. Chk1|0.9 nM (Ki)|Chk1|<1 nM (IC50)|Chk2|8 nM (IC50)
Prexasertib (LY2606368) is a potent and selective ATP competitive inhibitor of Chk1, with an IC50 of <1 nM, and also inhibits CHK2, with an IC50 of 8 nM. Prexasertib has an EC50 of 1 nM for CHK1 activity through autophosphorylation of serine 296 and <31 nM for HT-29 CHK2 autophosphorylation (S516). Prexasertib potently abrogates the G2-M checkpoint activated by doxorubicin in p53-deficient HeLa cells with an EC50 of 9 nM. However, 100 nM Prexasertib does not inhibit PMA-stimulated RSK but instead weakly stimulates phosphorylation of S6 on serines 235/236. Prexasertib is broadly antiproliferative with IC50s of 3 nM, 3 nM, 10 nM, 37 nM, and 68 nM against U-2 OS, Calu-6, HT-29, HeLa, and NCI-H460 cell lines, respectively. Prexasertib (4 nM) results in a large shift in cell-cycle populations from G1 and G2-M to S-phase with an accompanied induction of H2AX phosphorylation in U-2 OS cells[1]. Prexasertib (LY2606368; 25 μM) exhibits inhibitory activities against proliferation of AGS and MKN1 cells. Prexasertib (20 nM) inhibits HR repair capacity DR-GFP cells. Prexasertib (5 nM) in combination with PARP inhibitor BMN673, displays synergistic anticancer effects in gastric cancer cells[2].
Prexasertib (LY2606368; 15 mg/kg, s.c.) significantly inhibits tumor growth in xenograft tumor models with less animal weight loss[1]. Prexasertib (LY2606368; 2 mg/kg, s.c.) and BMN673 combination has synergistic anticancer effect in gastric cancer PDX model, and the effect is higher than that of one drug alone[2].
[1]. King C, et al. LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms. Mol Cancer Ther. 2015 Sep;14(9):2004-1 [2]. Yin Y, et al. Chk1 inhibition potentiates the therapeutic efficacy of PARP inhibitor BMN673 in gastric cancer. Am J Cancer Res. 2017 Mar 1;7(3):473-483.