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Purity: ≥98%
RMC-4550 (RMC4550) is a novel, potent, selective and allosteric inhibitor of SHP2 phosphatase with anticancer activity. With an IC50 of 0.583 nM, it inhibits SHP2. When researching SHP2's function in tumor biology in rodents, both in vitro and in vivo, RMC-4550 is an excellent tool compound. As a convergent signaling node, SHP2 can effectively target mutations in the RAS-MAPK pathway that are upstream (driven by RTK) or downstream (dependent on RAS-GTP). Numerous cancer types are driven by oncogenic changes in the RAS/RAF/MEK/ERK pathway. The majority of cancers caused by other pathway alterations, such as non-V600E oncogenic BRAF, RAS GTPase-activating protein (GAP), NF1 (neurofibromin 1) loss, and oncogenic KRAS, lack effective targeted therapies, despite the effectiveness of BRAF and MEK inhibitors against BRAFV600E-driven cancers.
| Targets |
SHP2 (IC50 = 0.583 nM)
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|---|---|
| ln Vitro |
RMC-4550 exhibits a cellular IC50 of 39 nM in PC9 cells with a pERK readout, and it inhibits purified, activated full length human SHP2 with an IC50 of 1.55 nM. Up to 10 µM, RMC-4550 exhibits no discernible inhibitory activity against the catalytic domain of SHP2, a panel of 468 protein kinases, and a panel of 14 additional protein phosphatases. RMC-4550 has a high passive permeability (458 nm/s), an efflux ratio of 1, and low to moderate cross species in vitro intrinsic clearance (3.6-24 µL/min/million cells) in hepatocytes[1].
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| ln Vivo |
RMC-4550 has a half-life that is suitable for once-daily oral administration and a moderate to high bioavailability. RMC-4550 exhibits dose-dependent efficacy consistent with target modulation in the EGFR-driven KYSE-520 human esophageal cancer xenograft model, as measured by phospho-ERK inhibition in tumors. In this model, RMC-4550 demonstrates good tolerance at dosages that result in both maximum and sustained efficacy [1].
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| Cell Assay |
In Biotin-free RPMI supplemented with 0.1% fetal bovine serum, 0.02% bovine serum albumin, and 1% penicillin/streptomycin, 30,000 HEK-293 cells per well are plated in 96-well plates. The induction of SOS1 constructs is achieved by adding 0.1 μg/mL doxycycline and waiting a full day. For one hour, cells are treated with three-fold dilutions of RMC-4550 serially diluted in biotin-free medium supplemented with 1% penicillin/streptomycin and 0.02% bovine serum albumin (final DMSO concentration equal to 0.1%). After the last five minutes of medication administration, cells are lysed, stimulated with 50 ng/mL EGF, and their ERK1/2 phosphorylation is examined.
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| Animal Protocol |
Female (6-8 week old) athymic nude mice implanted with NCI-H358 (Balb/c strain background) or MIA PaCa-2 (NCR nude strain background) tumor cells subcutaneously in the flank
3-60 mg/kg PO |
| References |
| Molecular Formula |
C21H26CL2N4O2
|
|---|---|
| Molecular Weight |
437.3627
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| Exact Mass |
436.14
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| Elemental Analysis |
C, 57.67; H, 5.99; Cl, 16.21; N, 12.81; O, 7.32
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| CAS # |
2172651-73-7
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| Related CAS # |
2172651-73-7
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| PubChem CID |
134183206
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| Appearance |
White to light yellow solid powder
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| LogP |
2.5
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
29
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| Complexity |
563
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| Defined Atom Stereocenter Count |
2
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| SMILES |
C[C@H]1[C@H](C2(CCN(CC2)C3=NC(=C(N=C3CO)C4=C(C(=CC=C4)Cl)Cl)C)CO1)N
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| InChi Key |
IKUYEYLZXGGCRD-ORAYPTAESA-N
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| InChi Code |
InChI=1S/C21H26Cl2N4O2/c1-12-18(14-4-3-5-15(22)17(14)23)26-16(10-28)20(25-12)27-8-6-21(7-9-27)11-29-13(2)19(21)24/h3-5,13,19,28H,6-11,24H2,1-2H3/t13-,19+/m0/s1
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| Chemical Name |
[3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl]methanol
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| Synonyms |
RMC-4550; RMC 4550; RMC4550
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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) |
Ethanol: 22~100 mg/mL (50.3~228.6 mM)
DMSO: ~11 mg/mL (~25.2 mM) |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.72 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 (5.72 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 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 (5.72 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 | 2.2864 mL | 11.4322 mL | 22.8645 mL | |
| 5 mM | 0.4573 mL | 2.2864 mL | 4.5729 mL | |
| 10 mM | 0.2286 mL | 1.1432 mL | 2.2864 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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