| Size | Price | Stock | Qty |
|---|---|---|---|
| 100mg |
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| 1g | |||
| Other Sizes |
| Targets |
GDC0575 monohydrochloride targets checkpoint kinase 1 (Chk1), a key regulator of the DNA damage response (DDR) that mediates cell cycle checkpoints in the S and G2/M phases. By inhibiting Chk1 with an IC50 of 1.2 nM, the compound abrogates chemotherapy-induced cell cycle arrest and induces mitotic catastrophe in DNA-damaged cells. The compound specifically binds to and inhibits Chk1, leading to tumor cells bypassing Chk1-dependent cell cycle checkpoints. This mechanism sensitizes cancer cells to DNA-damaging agents.
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| ln Vitro |
The buffered CHK1 activator GDC-0575 diHClide has an IC50 of 1.2 nM. GDC-0575 (100 nM) lowers the levels of phosphorylated CDK2 tyr15, which inhibits AraC-induced CHK1 activation []. AML cell viability is unaffected by GDC-0575 dihydrochloride (100 nM), however when used in conjunction with AraC, it can dramatically lower cell viability and promote tolerance. Normal hematopoietic stem cells (HSPCs) are unaffected by GDC-0575 dihydrochloride plus AraC [1]. Twenty melanoma cell lines were exposed to tumor cytotoxic activity by GDC-0575 dihydrochloride; however, some of the cell lines grown as spheres (TS) were comparatively insensitive [2].
GDC0575 (100 nM) lowers the levels of phosphorylated CDK2 tyr15, which inhibits AraC-induced CHK1 activation. The compound's potent inhibition of Chk1 (IC50 = 1.2 nM) has been demonstrated in enzymatic assays. By disrupting Chk1-mediated cell cycle checkpoints, GDC0575 forces DNA-damaged cells into mitosis. Its effects on cell cycle progression and DNA repair have been characterized in various cancer cell lines. |
| ln Vivo |
In the U937-Luc cell transplant paradigm, GDC-0575 dihydrochloride (7.5 mg/kg, po) in combination with AraC is more effective than AraC alone at removing the leukocyte load nearly entirely. In vivo AraC cytotoxicity is increased by GDC-0575 dihydrochloride in various primary AML types [1]. Tumor growth in D20 and C002 xenografts is dose-dependently inhibited by GDC-0575 dihydrochloride (25, 50 mg/kg, po) [2].
GDC0575 has been studied in models of colitis-associated cancer and colitis. As an orally bioavailable Chk1 inhibitor, it can be administered conveniently in preclinical models. The compound's ability to abrogate Chk1-dependent cell cycle checkpoints sensitizes tumor cells to DNA-damaging agents. Its in vivo efficacy has been demonstrated in various cancer models. Specific dosing regimens and detailed efficacy data are available in the scientific literature. |
| Enzyme Assay |
In vitro enzyme assays for GDC0575 involve measuring the inhibition of Chk1 kinase activity using purified Chk1 enzyme and appropriate substrates. The compound is incubated with Chk1 and a peptide substrate in the presence of ATP, and phosphorylation is measured using scintillation proximity assays, fluorescence polarization, or other detection methods. The IC50 value of 1.2 nM is determined from dose-response curves. Selectivity against other kinases is assessed using broad kinase profiling panels.
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| Cell Assay |
In vitro cell-based assays for GDC0575 involve treating cancer cell lines with varying concentrations of the compound to assess its effects on Chk1 signaling, cell cycle progression, and cell viability. Chk1 inhibition is confirmed by measuring phosphorylated CDK2 tyr15 levels using Western blotting. Cell cycle analysis is performed by flow cytometry. Cell viability is measured using MTT or similar assays. Combination studies with DNA-damaging agents (e.g., AraC) assess synergistic effects. Apoptosis is quantified using Annexin V/PI staining.
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| Animal Protocol |
In vivo animal experiments for GDC0575 have been conducted in models of cancer and colitis-associated cancer. Tumor-bearing mice are treated with GDC0575 orally, alone or in combination with chemotherapeutic agents. Tumor growth inhibition is monitored. Colitis models are used to assess the compound's effects on inflammation and cancer development. Efficacy endpoints include tumor volume reduction, histopathological analysis, and biomarker assessment (e.g., Chk1 phosphorylation, cell cycle markers). Pharmacokinetic studies are performed alongside efficacy studies.
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| ADME/Pharmacokinetics |
GDC0575 monohydrochloride is an orally bioavailable small-molecule Chk1 inhibitor. The compound has a molecular weight and formula consistent with its chemical structure. It is typically dissolved in DMSO for in vitro studies and can be formulated for oral administration in vivo. Its pharmacokinetic properties, including absorption, distribution, metabolism, and elimination, have been characterized in preclinical studies. The compound is typically stored under recommended conditions for research compounds.
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| Toxicity/Toxicokinetics |
Specific toxicity data for GDC0575 is characteristic of Chk1 inhibitors. As a cell cycle checkpoint inhibitor, the compound may have effects on normal proliferating tissues. The compound is generally well-tolerated at therapeutic doses in preclinical studies. Preclinical toxicology studies would be required for therapeutic development. Standard safety precautions should be taken when handling the compound in research settings.
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| References |
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| Additional Infomation |
GDC0575 monohydrochloride is a highly potent and selective Chk1 inhibitor with an IC50 of 1.2 nM. It is also known as ARRY-575 or RG7741. The compound abrogates Chk1-dependent cell cycle checkpoints, forcing DNA-damaged cells into mitosis. GDC0575 is orally bioavailable. It has been studied for colitis-associated cancer and colitis. The compound has potential applications in cancer therapy, particularly in combination with DNA-damaging agents.
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| Molecular Formula |
C16H21BRCLN5O
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|---|---|
| Molecular Weight |
414.72784113884
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| Exact Mass |
413.061
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| CAS # |
1196504-54-7
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| Related CAS # |
GDC-0575;1196541-47-5;GDC-0575 dihydrochloride;1657014-42-0
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| PubChem CID |
67045163
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| Appearance |
Typically exists as solid at room temperature
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
24
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| Complexity |
460
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C1C[C@H](CN(C1)C2=C3C(=CNC3=NC=C2Br)NC(=O)C4CC4)N.Cl
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| InChi Key |
GKZACMRNGHGLEJ-HNCPQSOCSA-N
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| InChi Code |
InChI=1S/C16H20BrN5O.ClH/c17-11-6-19-15-13(14(11)22-5-1-2-10(18)8-22)12(7-20-15)21-16(23)9-3-4-9;/h6-7,9-10H,1-5,8,18H2,(H,19,20)(H,21,23);1H/t10-;/m1./s1
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| Chemical Name |
N-[4-[(3R)-3-aminopiperidin-1-yl]-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]cyclopropanecarboxamide;hydrochloride
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4112 mL | 12.0560 mL | 24.1121 mL | |
| 5 mM | 0.4822 mL | 2.4112 mL | 4.8224 mL | |
| 10 mM | 0.2411 mL | 1.2056 mL | 2.4112 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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