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ARS-1630 (ARS1630) is the less active isomer of ARS-1620, which is a novel and potent inhibitor of mutant K-ras G12C found in patent WO 2015054572 A1. It might possess anticancer properties.
| Targets |
KRAS(G12C)
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|---|---|
| ln Vitro |
Recent research has revealed that KRASG12C may be druggable through allele-specific covalent targeting of Cys-12 close to an inducible allosteric switch II pocket (S-IIP). Since the S-IIP is only accessible in the GDP-bound state, the effectiveness of this strategy depends on KRASG12C actively cycling between its active-GTP and inactive-GDP conformations. In vitro, this approach shows promise for suppressing mutant KRAS [2].
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| References | |
| Additional Infomation |
ARS-1620 is a quinazoline derivative with chlorine and fluorine substituents at positions 6 and 8, respectively, a 2-fluoro-6-hydroxyphenyl group at position 7, and a 4-(propanoyl)piperazin-1-yl group at position 4. It is a highly potent, selective, and orally bioavailable covalent KRAS-G12C inhibitor that effectively inhibits the gene encoding the protein KRAS (Kirsten rat sarcoma virus) in cells and animals. It can be used as an inhibitor, antiviral agent, and antitumor agent. Recent studies have found that KRASG12C can be targeted by allele-specific covalent targeting of the Cys-12 site near the inducible allosteric switch II pocket (S-IIP). The success of this method relies on the dynamic cycling of KRASG12C between the active GTP-bound and inactive GDP-bound states, as S-IIP accessibility is limited to the GDP-bound state. This strategy has been shown to effectively inhibit mutant KRAS in vitro; however, its applicability in vivo remains uncertain. This article describes the design and identification of structure-based ARS-1620, a covalent compound with high efficiency and selectivity for KRASG12C. ARS-1620 can rapidly and persistently occupy its target in vivo, thereby inducing tumor regression. We used ARS-1620 to resolve the dependence on oncogenic KRAS and demonstrated that the monolayer cell culture model significantly underestimated the dependence on KRAS in vivo. This study provides in vivo evidence that mutant KRAS can be selectively targeted and reveals that ARS-1620 represents a new generation of KRASG12C-specific inhibitors with good therapeutic potential. [2]
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| Molecular Formula |
C21H17CLF2N4O2
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|---|---|
| Molecular Weight |
430.835090398788
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| Exact Mass |
430.1
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| CAS # |
1698055-86-5
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| Related CAS # |
ARS-1323; 1698024-73-5; ARS-1620; 1698055-85-4
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| PubChem CID |
137003167
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| Appearance |
White to yellow solid powder
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| LogP |
4
|
| Hydrogen Bond Donor Count |
1
|
| 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 |
636
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| Defined Atom Stereocenter Count |
0
|
| SMILES |
O=C(N1CCN(C2C3C(=C(C(C4C(O)=CC=CC=4F)=C(C=3)Cl)F)N=CN=2)CC1)C=C
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| InChi Key |
ZRPZPNYZFSJUPA-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H17ClF2N4O2/c1-2-16(30)27-6-8-28(9-7-27)21-12-10-13(22)17(19(24)20(12)25-11-26-21)18-14(23)4-3-5-15(18)29/h2-5,10-11,29H,1,6-9H2
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| Chemical Name |
1-[4-[6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one
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| Synonyms |
ARS1630;ARS 1630; ARS-1630
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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) |
DMSO: ≥ 100 mg/mL (~232.1 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.80 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 25.0 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: 2.5 mg/mL (5.80 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 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: ≥ 2.5 mg/mL (5.80 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 | 2.3210 mL | 11.6052 mL | 23.2105 mL | |
| 5 mM | 0.4642 mL | 2.3210 mL | 4.6421 mL | |
| 10 mM | 0.2321 mL | 1.1605 mL | 2.3210 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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