GDC-0575 (ARRY-575, RG7741) is a potent and selective oral inhibitor of cell cycle checkpoint kinase 1 (Chk1) with an IC50 of 1.2 nM. GDC-0575 abrogates DNA damage-induced S and G2–M checkpoints, exacerbates DNA double-strand breaks and induces apoptosis in STS cells. GDC-0575 has a synergistic or additive effect together with gemcitabine.
In vivo, GDC-0575 is active at 25 mg/kg as a single agent, but the efficacy is improved at the higher dose. GDC-0575 effectively blocks tumor growth in the D20 and C002 xenografts, and the effect is maintained for at least 10 days after the final dose is administered.
| Cell Experiment | |
|---|---|
| Cell lines | AML cell lines |
| Preparation method | AML cell lines are seeded at 1×104 cells/well in 96-well plates in triplicate, and subjected to different treatment conditions. After 24 h of incubation with GDC-0575, cell proliferation is measured with the XTT Cell Proliferation Kit II. |
| Concentrations | 100 nM |
| Incubation time | 24 h |
| Animal Experiment | |
|---|---|
| Animal models | Female nude BALB/c mice |
| Formulation | 0.5% w/v methylcellulose and 0.2%v/v Tween 80 |
| Dosages | 25 mg/kg, 50 mg/kg |
| Administration | oral gavage |
| Molecular Weight | 378.27 |
| Formula | C16H20BrN5O |
| CAS Number | 1196541-47-5 |
| Solubility (25°C) | DMSO 80 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
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| Zn-DPA-maytansinoid conjugate 1
Zn-DPA-maytansinoid conjugate 1 is a small molecule-based maytansinoid conjugate targeting immune checkpoint. |
| CHK1-IN-7
CHK1-IN-7 is a potent human CHK1 inhibitor. |
| Chk2-IN-1
Chk2-IN-1 (compound 1) is a potent and selective inhibitor of checkpoint kinase 2 (Chk2), with IC50s of 13.5 nM and 220.4 nM for Chk2 and Chk1, respectively. Chk2-IN-1 can elicit a strong ataxia telangiectasia mutated (ATM)-dependent Chk2-mediated radioprotection effect. |
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