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100mg | ||
250mg | ||
500mg |
ln Vitro |
JDQ-443, with IC50 values of 0.018 and 0.063 μM, respectively, enhances the proliferation of KRASG12C mutant cell lines NCI-H358 and NCI-H2122, while also promoting a dose-dependent drop in phosphorylated ERK (pERK) levels [2]. With low reversible binding affinity, JDQ443 covalently and selectively binds to the pocket of RAS switch II, inhibiting GDP-binding KRASG12C. This results in tunable inhibition of the regeneration of KRAS G12C/H95, G12C/R68S, and G12C/Y96 double mutant cell lines as well as KRASG12C mutants[2].
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ln Vivo |
JDQ443 (10-100 mg/kg, tumor, daily, for 14 days) demonstrated anti-activity and suppressed tumor growth in the KRAS G12C mutant CDX model in a dose-dependent manner [2]. JDQ443 (sidewall, 100 mg/kg), daily (JDQ443) + 7.5 mg/kg twice daily (TNO155) for 36 days) exhibited better cell growth inhibition when combination with single agent JDQ443 or cell killing effect[2]. Tumor resistance categorization was created in PDX models of NSCLC and colorectal cancers and enhanced by combined therapy with various medications [2].
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References |
[1]. LIU BO, et al. PYRAZOLYL DERIVATIVES USEFUL AS ANTI-CANCER AGENTS. Patent WO2021120890A1.
[2]. Weiss A, Lorthiois E, Barys L, et al. Discovery, Preclinical Characterization, and Early Clinical Activity of JDQ443, a Structurally Novel, Potent and Selective, Covalent Oral Inhibitor of KRASG12C. Cancer Discov. 2022;candisc.0158.2022. |
Molecular Formula |
C29H28CLN7O
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Molecular Weight |
526.03
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Exact Mass |
525.2043862
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CAS # |
2653994-10-4
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Related CAS # |
Opnurasib;2653994-08-0
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Appearance |
solid
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SMILES |
CC1=CC2=C(C=NN2)C(=C1Cl)C3=C(N(N=C3C4=CC5=C(C=C4)N(N=C5)C)C6CC7(C6)CN(C7)C(=O)C=C)C
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InChi Key |
AZUYLZMQTIKGSC-UHFFFAOYSA-N
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InChi Code |
InChI=1S/C29H28ClN7O/c1-5-24(38)36-14-29(15-36)10-20(11-29)37-17(3)25(26-21-13-31-33-22(21)8-16(2)27(26)30)28(34-37)18-6-7-23-19(9-18)12-32-35(23)4/h5-9,12-13,20H,1,10-11,14-15H2,2-4H3,(H,31,33)
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Chemical Name |
1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one
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Synonyms |
(S)-NVP-JDQ443; (S)-JDQ-443
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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 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.) |
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Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 1.9010 mL | 9.5052 mL | 19.0103 mL | |
5 mM | 0.3802 mL | 1.9010 mL | 3.8021 mL | |
10 mM | 0.1901 mL | 0.9505 mL | 1.9010 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.
JDQ443 has selective activity for KRASG12C, including H95 double mutants, and shows dose-dependent single-dose pharmacokinetics and pharmacodynamics in mouse tumor models. Cancer Discov . 2022 Jun 2;12(6):1500-1517. td> |
JDQ443 displays antitumor activity across a range of cell-derived, KRASG12C-dependent mouse tumor models, with efficacy driven by daily AUC. Cancer Discov . 2022 Jun 2;12(6):1500-1517. td> |
JDQ443 generates categorical antitumor responses in PDX models of NSCLC and colorectal tumors that are improved by combination treatment with other agents. Cancer Discov . 2022 Jun 2;12(6):1500-1517. td> |
JDQ443 plus TNO155 improves the single-agent activity of JDQ443 in CDX models, with efficacy maintained with lower doses of either drug. Cancer Discov . 2022 Jun 2;12(6):1500-1517. td> |