LY 2606368
LY 2606368 Basic information
- Product Name:
- LY 2606368
- Synonyms:
-
- LY 2606368
- 5-((5-(2-(3-aminopropoxy)-6-methoxyphenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile LY2606368
- 5-[[5-[2-(3-Aminopropoxy)-6-methoxyphenyl]-1H-pyrazol-3-yl]amino]-2-pyrazinecarbonitrile
- 5-((5-(2-(3-aminopropoxy)-6-methoxyphenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile
- Prexasertib
- LY 2606368;LY-2606368;PREXASERTIB
- Prexasertib (LY2606368)
- CS-1453
- CAS:
- 1234015-52-1
- MF:
- C18H19N7O2
- MW:
- 365.39
- Mol File:
- 1234015-52-1.mol
LY 2606368 Chemical Properties
- Boiling point:
- 608.5±55.0 °C(Predicted)
- Density
- 1.37±0.1 g/cm3(Predicted)
- storage temp.
- Store at -20°C
- solubility
- insoluble in DMSO
- form
- A crystalline solid
- pka
- 11.89±0.10(Predicted)
- color
- Light yellow to brown
- InChI
- InChI=1S/C18H19N7O2/c1-26-14-4-2-5-15(27-7-3-6-19)18(14)13-8-16(25-24-13)23-17-11-21-12(9-20)10-22-17/h2,4-5,8,10-11H,3,6-7,19H2,1H3,(H2,22,23,24,25)
- InChIKey
- DOTGPNHGTYJDEP-UHFFFAOYSA-N
- SMILES
- C1(C#N)=NC=C(NC2C=C(C3=C(OC)C=CC=C3OCCCN)NN=2)N=C1
LY 2606368 Usage And Synthesis
Description
LY2606368 is a checkpoint kinase 1 (Chk1) inhibitor with a Ki value of 0.9 nM against the purified target and IC50 values of <13 nM in a viability study of multiple colorectal cancer cell lines. Inhibition of Chk1 causes double-strand DNA breakage in cells leading to an excessive cell damage burden and subsequent cell death. In vitro, LY2606368 inhibits the doxorubicin-activated G2/M checkpoint in p53-deficient HeLa cells with an EC50 value of 9 nM. LY2606368, at 25 nM, also significantly induces apoptosis and inhibits colony formation in AGS and MKN1 gastric cancer cells.
Uses
LY 2606368 is a novel CHK1 inhibitor under investigation as a chemopotentiating agent. It causes double-stranded DNA breakage while simultaneously removing the protection of the DNA damage checkpoints. LY 2606368 is representative of a novel class of drugs for the treatment of cancer and tumor growth inhibition.
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[1].
Prexasertib (15 mg/kg; SC) causes CHK1 inhibition in the blood and the phosphorylation of both H2AX (S139) and RPA2 (S4/S8)[1].
| Animal Model: | Female CD-1 nu-/nu- mice (26-28 g) with Calu-6 cells[1] |
| 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[1] |
| 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. |
IC 50
Chk1: 0.9 nM (Ki); Chk1: <1 nM (IC50); Chk2: 8 nM (IC50)
References
[1] wu w, bi c, bence a k, et al. antitumor activity of chk1 inhibitor ly2606368 as a single agent in sw1990 human pancreas orthotopic tumor model. cancer research, 2012, 72(8 supplement): 1776.
[2] lainchbury m, matthews t p, mchardy t, et al. discovery of 3-alkoxyamino-5-(pyridin-2-ylamino) pyrazine-2-carbonitriles as selective, orally bioavailable chk1 inhibitors. journal of medicinal chemistry, 2012, 55(22): 10229-10240.
[3] mcneely s c, burke t f, durlandbusbice s, et al. abstract a108: ly2606368, a second generation chk1 inhibitor, inhibits growth of ovarian carcinoma xenografts either as monotherapy or in combination with standard-of-care agents. molecular cancer therapeutics, 2011, 10(supplement 1): a108.
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