| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
| Targets |
KRas G12C
|
|---|---|
| ln Vitro |
In several KRAS mutant cancer cells (NCI-H2030, MIA PaCa-2, SW1573, NCI-H23, and NCI-H358 cells), LC-2 causes endogenous KRASG12C to degrade, with DC50s ranging from 0.25 to 0.76 μM. A genuine PROTAC mechanism drives the degradation of KRASG12C induced by LC-2. Treatment with 2.5 μM of LC-2 is applied to MIA PaCa-2, NCI-H23, and SW1573 cells for 6, 24, 48, and 72 hours. Maximum KRAS degradation happened in less than 24 hours and continued for up to 72 hours in all three cell lines[1].
In homozygous and heterozygous KRAS mutant cell lines, LC-2-induced (2.5 μM; 6-24 hours) KRAS G12C degradation modifies Erk signaling[1]. |
| References | |
| Additional Infomation |
The KRAS gene is mutated in about 20% of human cancers. Although it was historically considered "untreatable," it remains one of the most promising targets in the field of drug regulation. In recent years, the discovery of potent covalent inhibitors of KRASG12C mutants has sparked a new wave of research on small molecule drugs targeting KRAS. Although these inhibitors have shown promising clinical results, we hope to explore PROTAC-mediated degradation as a complementary strategy to regulate mutant KRAS. This article reports the development of LC-2, the first PROTAC capable of degrading endogenous KRASG12C. LC-2 covalently binds to KRASG12C through the MRTX849 active group and recruits the E3 ubiquitin ligase VHL, thereby inducing rapid and sustained degradation of KRASG12C, ultimately inhibiting the MAPK signaling pathway in homozygous and heterozygous KRASG12C cell lines. LC-2 demonstrates that PROTAC-mediated degradation is a feasible method to reduce the level of oncogenic KRAS and its downstream signaling in cancer cells. [1]
|
| Molecular Formula |
C34H37CLFN7O4
|
|---|---|
| Molecular Weight |
662.15
|
| Exact Mass |
661.257
|
| CAS # |
2561529-96-0
|
| Related CAS # |
2561529-96-0
|
| PubChem CID |
156613479
|
| Appearance |
Light yellow to yellow solid
|
| LogP |
2.3
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
11
|
| Rotatable Bond Count |
10
|
| Heavy Atom Count |
47
|
| Complexity |
1190
|
| Defined Atom Stereocenter Count |
2
|
| SMILES |
C=C(C(=O)N1CCN(C[C@@H]1CC#N)C2=NC(=NC3=C2CCN(C3)C4=CC=CC5=C4C(=CC=C5)Cl)OC[C@@H]6CCCN6CCC(=O)O)F
|
| InChi Key |
CWTHNCSWSDACRS-DQEYMECFSA-N
|
| InChi Code |
InChI=1S/C34H37ClFN7O4/c1-22(36)33(46)43-18-17-42(19-24(43)10-13-37)32-26-11-15-41(29-9-3-6-23-5-2-8-27(35)31(23)29)20-28(26)38-34(39-32)47-21-25-7-4-14-40(25)16-12-30(44)45/h2-3,5-6,8-9,24-25H,1,4,7,10-12,14-21H2,(H,44,45)/t24-,25-/m0/s1
|
| Chemical Name |
3-[(2S)-2-[[7-(8-chloronaphthalen-1-yl)-4-[(3S)-3-(cyanomethyl)-4-(2-fluoroprop-2-enoyl)piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidin-1-yl]propanoic acid
|
| Synonyms |
MRTX849 acid; MRTX849 acid; 2561529-96-0; EX-A5368; AKOS040757850; 3-[(2S)-2-[[7-(8-chloronaphthalen-1-yl)-4-[(3S)-3-(cyanomethyl)-4-(2-fluoroprop-2-enoyl)piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidin-1-yl]propanoic acid;
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage. (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO: ~130 mg/mL (~196.3 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3.25 mg/mL (4.91 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 32.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5102 mL | 7.5512 mL | 15.1023 mL | |
| 5 mM | 0.3020 mL | 1.5102 mL | 3.0205 mL | |
| 10 mM | 0.1510 mL | 0.7551 mL | 1.5102 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT04793958 | Recruiting | Biological: Cetuximab Drug: MRTX849 |
Advanced Colorectal Cancer Metastatic Colorectal Cancer |
Mirati Therapeutics Inc. | March 15, 2021 | Phase 3 |
|
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