| Size | Price | Stock | Qty |
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| 5mg |
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| Other Sizes |
| Targets |
KRAS G12C (DC50 = 0.25~0.76 μM); VHL
The target of LC-2 is KRASG12C, and it recruits the E3 ligase VHL. LC-2 targets KRASG12C, a mutant form of the KRAS GTPase that is commonly found in various cancers. As a PROTAC, LC-2 binds to KRASG12C through the MRTX849 warhead and recruits the VHL E3 ubiquitin ligase. This leads to ubiquitination and proteasomal degradation of KRASG12C, suppressing MAPK signaling. KRAS is mutated in approximately 20% of human cancers. |
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| ln Vitro |
LC-2 covalently binds to KRASG12C via a MRTX849 warhead and recruits the E3 ligase VHL, inducing rapid and sustained degradation of endogenous KRASG12C in both homozygous and heterozygous KRASG12C cell lines. This degradation leads to the suppression of MAPK signaling, as evidenced by reduced levels of phosphorylated ERK (pERK) [2]
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 a DC50 range from 0.25 to 0.76 μM. KRASG12C is degraded by LC-2 through a genuine PROTAC mechanism. 2.5 μM LC-2 was applied to MIA PaCa-2, NCI-H23, and SW1573 cells during 6, 24, 48, and 72 hours. Maximum KRAS degradation starts in 24 hours and lasts for up to 72 hours in all three cell lines [1]. In both heterozygous and homozygous KRAS mutant cell lines, Erk signaling is influenced by LC-2-induced (2.5 μM; 6-24 hours) KRAS G12C degradation [1]. In vitro, LC-2 degrades endogenous KRASG12C with DC50s between 0.25 µM and 0.76 µM. It inhibits MAPK signaling in both pure and heterozygous KRASG12C cell lines. LC-2 demonstrates that PROTAC-mediated degradation is a viable option for attenuating oncogenic KRAS levels and downstream signaling in cancer cells. The compound shows potent degradation activity in cellular assays. |
| ln Vivo |
In vivo activity data for LC-2 are not extensively detailed in the available sources. The compound is a research tool for studying KRASG12C degradation. Specific in vivo efficacy data in animal models have not been reported. The compound may be used to explore therapeutic strategies targeting KRAS-mutant cancers.
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| Enzyme Assay |
Competition, Proteasome Inhibition, and Neddylation Inhibition Experiments [2]
Between 2.5 x 105 and 5.0 x 105 cells were seeded into 6-well plates. The next day cells were pretreated with DMSO, 500 μM or 1 mM VHL ligand, 1 μM epoxomicin, 1 μM MLN4924, or 100 nM M bafilomycin A1 for 1 h. Media was then removed and cells were treated with DMSO, 2.5 μM LC-2 plus DMSO, 2.5 μM LC-2 Epimer plus DMSO, or cotreated with 2.5 μM LC-2 and the corresponding competitor/inhibitor. NCI-H2030 cells were treated for 4 h and NCI-H23 cells were treated for 24 h, after which cells were lysed by scraping in RIPA buffer supplemented as described previously. For an individual experiment conducted on a given day, two separate wells of cells were treated identically for every condition and harvested side-by-side. The in vitro degradation assay for LC-2 involves measuring the reduction in KRASG12C protein levels. Cells (e.g., KRASG12C-mutant cancer cell lines) are treated with LC-2 at varying concentrations for a defined period. Protein levels are quantified by Western blotting using KRAS-specific antibodies. DC50 values are calculated from dose-response curves (0.25-0.76 µM). |
| Cell Assay |
Western blot analysis[1]
Cell Types: MIA PaCa-2 cells and NCI-H23 cells Tested Concentrations: 2.5 μM Incubation Duration: 6-24 hrs (hours) Experimental Results: Inhibition and degradation of KRAS G12C reduces homozygous MIA PaCa at 6 and 24 hrs (hours) pErk Signaling-2 Cells Cells (homozygous and heterozygous KRASG12C lines) were treated with LC-2 at specified concentrations. Following treatment, cell lysates were prepared, and Western blot analysis was performed to detect levels of KRASG12C and phosphorylated ERK (pERK), allowing assessment of KRASG12C degradation and suppression of MAPK signaling [2] Cellular assays are performed using KRASG12C-mutant cancer cell lines. Cells are treated with LC-2 at varying concentrations. MAPK signaling is assessed by measuring the phosphorylation of ERK1/2 by Western blotting. Cell proliferation and viability are assessed using standard assays. |
| Animal Protocol |
In vivo animal studies for LC-2 are not detailed in the available sources. The compound is a research tool for studying KRASG12C degradation. Specific animal models, dosing regimens, and efficacy data have not been reported.
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| ADME/Pharmacokinetics |
Pharmacokinetic data for LC-2 are not available in the provided sources. The compound has a molecular weight of 1132.78 g/mol. It is soluble in DMSO at 100 mg/mL but is insoluble in water and ethanol. For in vivo administration, homogeneous suspensions can be prepared in CMC-Na at ≥5 mg/mL. Specific PK parameters have not been reported.
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| Toxicity/Toxicokinetics |
Toxicity data for LC-2 are not reported in the available sources. As a research compound, it is not intended for therapeutic use. Specific toxicological profiles have not been characterized.
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| References | |
| Additional Infomation |
LC-2 is the first PROTAC capable of degrading endogenous KRASG12C. Its design utilizes the MRTX849 active group to covalently bind to KRASG12C and binds a group that can recruit the E3 ligase VHL, thereby achieving targeted degradation of the oncogenic mutant KRASG12C, as a supplementary strategy to existing KRASG12C inhibitors [2]. KRAS is mutated in about 20% of human cancers. Although it was historically considered "undruggable," 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. Despite the promising clinical prospects of these inhibitors, 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 via the MRTX849 warhead and recruits the E3 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 approach to reduce the level of oncogenic KRAS and its downstream signaling in cancer cells. [2]
LC-2 is a research compound for studying KRASG12C degradation in cancer research. It is a first-in-class PROTAC that degrades endogenous KRASG12C. The compound is available from commercial suppliers for research use only. It demonstrates that PROTAC-mediated degradation is a viable approach for targeting oncogenic KRAS. |
| Molecular Formula |
C59H71CLFN11O7S
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|---|---|
| Molecular Weight |
1132.78095459938
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| Exact Mass |
1131.493
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| Elemental Analysis |
C, 62.56; H, 6.32; Cl, 3.13; F, 1.68; N, 13.60; O, 9.89; S, 2.83
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| CAS # |
2502156-03-6
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| Related CAS # |
Adagrasib;2326521-71-3
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| PubChem CID |
154727765
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| Appearance |
Off-white to brown solid
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| Density |
1.3±0.1 g/cm3
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| Index of Refraction |
1.614
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| LogP |
3.07
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
16
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| Rotatable Bond Count |
21
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| Heavy Atom Count |
80
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| Complexity |
2170
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| Defined Atom Stereocenter Count |
5
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| SMILES |
ClC1=CC=CC2C=CC=C(C=21)N1CC2=C(CC1)C(=NC(=N2)OC[C@@H]1CCCN1CCCOCCC(N[C@H](C(N1C[C@@H](C[C@H]1C(NCC1C=CC(C2=C(C)N=CS2)=CC=1)=O)O)=O)C(C)(C)C)=O)N1CCN(C(C(=C)F)=O)[C@@H](CC#N)C1
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| InChi Key |
ZCGQZLKPUVGCBQ-HLMPTVQRSA-N
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| InChi Code |
InChI=1S/C59H71ClFN11O7S/c1-37(61)56(76)71-27-26-70(32-42(71)19-22-62)54-45-20-25-69(48-14-7-11-40-10-6-13-46(60)51(40)48)34-47(45)65-58(67-54)79-35-43-12-8-23-68(43)24-9-28-78-29-21-50(74)66-53(59(3,4)5)57(77)72-33-44(73)30-49(72)55(75)63-31-39-15-17-41(18-16-39)52-38(2)64-36-80-52/h6-7,10-11,13-18,36,42-44,49,53,73H,1,8-9,12,19-21,23-35H2,2-5H3,(H,63,75)(H,66,74)/t42-,43-,44+,49-,53+/m0/s1
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| Chemical Name |
(2S,4R)-1-((S)-2-(3-(3-((S)-2-(((7-(8-chloronaphthalen-1-yl)-4-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)pyrrolidin-1-yl)propoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide
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| Synonyms |
LC2; LC 2; LC-2; (2S,4R)-1-((S)-2-(3-(3-((S)-2-(((7-(8-Chloronaphthalen-1-yl)-4-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)pyrrolidin-1-yl)propoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; PROTAC KRASG12C Degrader-LC-2; CHEMBL5174597; LC-2
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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 : ~50 mg/mL (~44.14 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (1.84 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 20.8 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: 2.08 mg/mL (1.84 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 20.8 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.8828 mL | 4.4139 mL | 8.8278 mL | |
| 5 mM | 0.1766 mL | 0.8828 mL | 1.7656 mL | |
| 10 mM | 0.0883 mL | 0.4414 mL | 0.8828 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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