Prexasertib

SKU: orb1226713

Description

A potent, selective, ATP-competitive inhibitor of CHK1 with Ki of 0.9 nM; potently abrogates the G2-M checkpoint activated by doxorubicin in p53-deficient HeLa cells with EC50 of 9 nM; causes replication catastrophe in vitro and in vivo; shows significant tumor growth inhibition in xenograft tumor models.Lung Cancer Phase 2 Clinical(In Vitro):Prexasertib (LY2606368) inhibits MELK (IC50=38 nM), SIK (IC50=42 nM), BRSK2 (IC50=48 nM), ARK5 (IC50=64 nM). LY2606368 requires CDC25A and CDK2 to cause DNA damage.Prexasertib (33, 100 nM; for 7 hours) results in DNA damage during S-phase in HeLa cells.Prexasertib (8-250 nM; pre-treated for 15 minutes) inhibits CHK1 autophosphorylation (S296) and CHK2 autophosphorylation (S516) in HT-29 cells.Prexasertib (4 nM; 24 hours) 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.Prexasertib (33 nM; for 12 hours) causes chromosomal fragmentation in HeLa cells. Prexasertib (100 nM; 0.5 to 9 hours) induces replication stress and depletes the pool of available RPA2 for binding to DNA.(In Vivo):Prexasertib (LY2606368; 1-10 mg/kg; SC; twice daily for 3 days, rest 4 days; for three cycles) causes growth inhibition in tumor xenografts.Prexasertib (15 mg/kg; SC) causes CHK1 inhibition in the blood and the phosphorylation of both H2AX (S139) and RPA2 (S4/S8).

Key Properties

• CAS Number: 1234015-52-1
• MW: 365.3892
• Purity: >98% (HPLC)
• Formula: C₁₈H₁₉N₇O₂
• SMILES: COC1=C(C(=CC=C1)OCCCN)C2=CC(=NN2)NC3=NC=C(N=C3)C#N
• Target: Chk
• Solubility: DMSO: ≥ 60 mg/mL

Bioactivity

• In Vivo:
  Prexasertib (LY2606368; 1-10 mg/kg; SC; twice daily for 3 days, rest 4 days; for three cycles) causes growth inhibition in tumor xenografts. Prexasertib (15 mg/kg; SC) causes CHK1 inhibition in the blood and the phosphorylation of both H2AX (S139) and RPA2 (S4/S8). Animal model: Female CD-1 nu-/nu-mice (26-28 g) with Calu-6 cells. Dosage: 1, 3.3, or 10 mg/kg. Administration: SC; twice daily for 3 days, rest 4 days; for three cycles. Result: Caused statistically significant tumor growth inhibition (up to 72.3%). Animal model: Female CD-1 nu-/nu-mice (26-28 g) with Calu-6 cells. Dosage: 15 mg/kg (Pharmacokinetic Analysis). Administration: SC (200 μL). Result: CHK1 was 7 ng/mL at 12 hours and 3 ng/mL by 24 hours in plasma exposures. Phosphorylation of both H2AX (S139) and RPA2 (S4/S8) was detectable at 4 hours, showing the rapid occurrence of DNA damage.
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• In Vitro:
  Prexasertib (LY2606368) inhibits MELK (IC50 = 38 nM), SIK (IC50 = 42 nM), BRSK2 (IC50 = 48 nM), ARK5 (IC50 = 64 nM). LY2606368 requires CDC25A and CDK2 to cause DNA damage. Prexasertib (33, 100 nM; for 7 hours) results in DNA damage during S-phase in HeLa cells. Prexasertib (8-250 nM; pre-treated for 15 minutes) inhibits CHK1 autophosphorylation (S296) and CHK2 autophosphorylation (S516) in HT-29 cells. Prexasertib (4 nM; 24 hours) 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. Prexasertib (33 nM; for 12 hours) causes chromosomal fragmentation in HeLa cells. Prexasertib (100 nM; 0.5 to 9 hours) induces replication stress and depletes the pool of available RPA2 for binding to DNA. Cell Cycle Analysis Cell line: HeLa cells. Concentration: 33, 100 nM. Incubation time: For 7 hours. Result: Had an IC50 of 37 nM and resulted in the G2-M population received DNA damage during S-phase but continued to progress through the cell cycle into an early mitosis. Western blot analysis. Cell line: HT-29 cells. Concentration: 8, 16, 31, 63, 125, 250 nM. Incubation time: Pre-treated for 15 minutes. Result: Inhibited CHK1 autophosphorylation (S296) and CHK2 autophosphorylation (S516) (IC50 of less than 31 nM) in HT-29 cells.
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Storage & Handling

• Storage: Storage temperature: -20°C. Stability: ≥ 2 years
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

LY-2606368 | LY 2606368 | LY2606368

Quick Database Links

Gene Symbol

Chk