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| ln Vitro |
Camonsertib (RP-3500; 1 μM; 1-24 hours) inhibits CHK1 (Ser345) phosphorylation for 1 to 3 hours [1]. Camonsertib inhibits gemcitabine-stimulated ATR phosphorylation of its substrate pCHK1 (Ser345), based on Western Blot analysis of LoVo cells [1]
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| ln Vivo |
Camonsertib (RP-3500; 3, 7, 15 mg/kg; lateral; once daily for 18 days) produces dose-dependent tumor growth inhibition in LoVo xenografts with a minimum effective dose (MED) of 7 mg/kg [Camonsertib (5, 10 mg/kg; vascular; once daily) produces statistically significant tumor growth inhibition in the CW-2 floating xenograft model [1]. Camonsertib (7 mg/kg; for 7 days) is claimed to elicit 8.1-fold and 2.7-fold stimulation of KAP1 and DNA-PKcs phosphorylation in mice with LoVo tumors [1]. High-dose Camonsertib tumors, 3 days on/4 days off (30 mg/kg) and 5 days on/2 days off (25 mg/kg), showed greater incidental anti-tumor effects compared with continuous dosing, daily A lower dose formulation (10 mg/kg) for 14 days [1]. /kg) in conjunction with PARPi Olaparib (80mg/kg; both medications on days 1-3 on/4 days off) or sequential (PARPi on for 3 days, then RP-3500 on 3 days, then 1 day) with sequential In contrast, schedules produce greater anti-tumor effects when affecting intolerance [1].
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| Cell Assay |
Western Blot analysis
Tested Concentrations: 1 μM Incubation Duration: 1, 2, 4, 6, 8, 16, 24, IC50 was 0.33 nM[1]. Hourly Experimental Results: CHK1(Ser345) phosphorylation is inhibited for 1 to 3 hrs (hours). Beginning at 4 hrs (hours), CHK1(Ser345) is re-phosphorylated as DNA-PKcs and its substrates KAP1 and H2AX are activated in treated cells. |
| Animal Protocol |
Animal/Disease Models: Female mice (6-8 weeks old) bearing LoVo xenografts [1]
Doses: 3, 7, 15 mg/kg (0.5% methylcellulose/0.02% SDS vehicle) Route of Administration: Oral; one time/day for 18 days Experimental Results: Produced dose-dependent tumor growth inhibition with a minimum effective dose (MED) of 7 mg/kg. The maximum tolerated dose (MTD) is 10 mg/kg, one time/day, continuously. |
| References | |
| Additional Infomation |
Camonsertib is a pyrazolopyridine that is 1H-pyrazolo[3,4-b]pyridine substituted by 1H-pyrazol-3-yl, (3-endo)-3-hydroxy-8-oxabicyclo[3.2.1]octan-3-yl, and (3R)-3-methylmorpholin-4-yl groups at positions 1, 4 and 6, respectively. It is a highly potent and selective inhibitor of ATR kinase (IC50 = 1 nM). It has a role as an antineoplastic agent and an EC 2.7.11.1 (non-specific serine/threonine protein kinase) inhibitor. It is a member of morpholines, a member of imidazoles, a pyrazolopyridine, a tertiary alcohol and an oxabicycloalkane.
Camonsertib is an orally available inhibitor of ataxia telangiectasia and Rad3 related (ATR) kinase, with potential antineoplastic activity. Upon oral administration, camonsertib selectively targets and inhibits ATR activity and blocks the downstream phosphorylation of the serine/threonine protein kinase checkpoint kinase 1 (CHK1). This prevents ATR-mediated signaling, which results in the inhibition of DNA damage checkpoint activation, the disruption of DNA damage repair, and the induction of tumor cell apoptosis. ATR, a serine/threonine protein kinase upregulated in a variety of cancer cell types, plays a key role in DNA repair, cell cycle progression and survival. It is activated by DNA damage caused during DNA replication-associated stress. |
| Molecular Formula |
C21H26N6O3
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|---|---|
| Molecular Weight |
410.47
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| Exact Mass |
410.206
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| CAS # |
2417489-10-0
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| PubChem CID |
156487652
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| Appearance |
White to off-white solid powder
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| LogP |
1.6
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
30
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| Complexity |
628
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| Defined Atom Stereocenter Count |
3
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| SMILES |
OC1(CC2CCC(O2)C1)C1C=C(N2CCOCC2C)N=C2N(C3=NNC=C3)N=CC=12
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| InChi Key |
YIHHYCIYAIVQKX-YNOVCBQDSA-N
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| InChi Code |
InChI=1S/C21H26N6O3/c1-13-12-29-7-6-26(13)19-8-17(21(28)9-14-2-3-15(10-21)30-14)16-11-23-27(20(16)24-19)18-4-5-22-25-18/h4-5,8,11,13-15,28H,2-3,6-7,9-10,12H2,1H3,(H,22,25)/t13-,14-,15+,21?/m1/s1
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| Chemical Name |
(1R,5S)-3-[6-[(3R)-3-methylmorpholin-4-yl]-1-(1H-pyrazol-5-yl)pyrazolo[3,4-b]pyridin-4-yl]-8-oxabicyclo[3.2.1]octan-3-ol
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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) |
DMSO : ~50 mg/mL (~121.81 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.25 mg/mL (3.05 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 1.25 mg/mL (3.05 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 1.25 mg/mL (3.05 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4362 mL | 12.1812 mL | 24.3623 mL | |
| 5 mM | 0.4872 mL | 2.4362 mL | 4.8725 mL | |
| 10 mM | 0.2436 mL | 1.2181 mL | 2.4362 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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