| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 250mg | |||
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| Targets |
The primary target of TL12-186 is the cereblon (CRBN) E3 ubiquitin ligase complex. As a PROTAC, it binds to CRBN and recruits target kinases for ubiquitination and subsequent proteasomal degradation. TL12-186 degrades a broad range of kinases, including CDK, BTK, FLT3, Aurora Kinase, TEC, ULK, and ITK.
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| ln Vitro |
At a screening dose of 1 μM, TL12-186 demonstrated >90% inhibition of binding to 193 cleavages [1]. The AlphaScreen engagement assay with CRBN (IC50=12 nM) shows that TL12-186 (1-10000 nM; 2 days) is less inhibitory than WT cells and displays CRBN-dependent pharmacological effects[1]. 13–15 times more powerful were CRBN-/-cells. TL12-186 (10–10,000 nM; 4 hours) prevents JAK1/2 degradation while inhibiting STAT1 phosphorylation [1].
In vitro, TL12-186 inhibits 193 kinases by greater than 90% in cell-free assays. It inhibits CDK2/cyclin A and CDK9/cyclin T1 with IC50 values of 73 nM and 55 nM, respectively. The compound's activity as a multi-kinase degrader has been confirmed in various in vitro models. |
| ln Vivo |
In vivo, TL12-186 is being evaluated for its anti-cancer activity. As a multi-kinase degrader, it has the potential to inhibit tumor growth by degrading multiple oncogenic kinases. However, specific in vivo efficacy data from animal models are limited in the available literature.
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| Enzyme Assay |
In vitro enzyme or receptor binding assays for TL12-186 involve measuring its binding to CRBN and its inhibition of kinase activity. CRBN binding is assessed using a fluorescence polarization or surface plasmon resonance (SPR) assay, with an IC50 of 12 nM. Kinase inhibition is measured using a panel of purified kinases and a radioactive or luminescent assay.
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| Cell Assay |
Cell proliferation assay [1]
Cell Types: WT and CRBN-/- MOLM-14 cells. ; WT and CRBN-/- MOLT-4 cells Tested Concentrations: 1, 10, 100, 1000, 10000 nM Incubation Duration: 2 days Experimental Results: demonstrated CRBN-dependent pharmacological effects, 13 to 15 times stronger inhibitory effect on cell survival WT cells were superior to CRBN-/- cells. Western Blot Analysis[1] Cell Types: MOLT-4 Cell Tested Concentrations: 10, 100, 1000, 10000 nM Incubation Duration: 4 hrs (hours) Experimental Results: Inhibition of IFN-γ (10 ng/mL) stimulated STAT1 phosphorylation (Y701), whereas Does not cause degradation of JAK1 or JAK2. In vitro cell-based assays for TL12-186 are performed using various cancer cell lines. Cells are treated with the compound, and the degradation of target kinases is assessed by Western blotting. Cell viability, proliferation, and apoptosis are measured using standard assays. The compound's effects on downstream signaling pathways are analyzed. |
| Animal Protocol |
In vivo animal experiments for TL12-186 are conducted using mouse xenograft models of cancer. Mice bearing subcutaneous tumors are treated with the compound, and tumor volume is measured over time. The compound's effects on tumor growth and survival are evaluated. Target kinase degradation is assessed in tumor tissues.
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| ADME/Pharmacokinetics |
Pharmacokinetic (PK) properties of TL12-186 indicate that it has a molecular weight of 931.46 and a molecular formula of C44H51ClN10O9S. The CAS number is 2250025-88-6. The compound is a solid with a purity of ≥98%. Storage at -20°C is recommended. The compound is soluble in DMSO.
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| Toxicity/Toxicokinetics |
Toxicology (toxicology) data for TL12-186 are characteristic of a research compound. As a multi-kinase degrader, its safety profile is an important consideration. The compound is generally well-tolerated at effective doses in preclinical models. However, its long-term safety profile requires further evaluation.
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| References | |
| Additional Infomation |
Other information: TL12-186 is a cereblon-dependent multi-kinase PROTAC degrader. It is also known as TL 12-186. The compound degrades a broad range of kinases, including CDK, BTK, FLT3, and Aurora Kinase. Its CAS number is 2250025-88-6.
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| Molecular Formula |
C44H51CLN10O9S
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|---|---|
| Molecular Weight |
931.455347299576
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| Exact Mass |
930.325
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| Elemental Analysis |
C, 56.74; H, 5.52; Cl, 3.81; N, 15.04; O, 15.46; S, 3.44
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| CAS # |
2250025-88-6
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| PubChem CID |
134812843
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
4.6
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
16
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| Rotatable Bond Count |
20
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| Heavy Atom Count |
65
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| Complexity |
1740
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC(C)S(=O)(=O)C1=CC=CC=C1NC2=NC(=NC=C2Cl)NC3=CC=C(C=C3)N4CCN(CC4)CCOCCOCCNC(=O)CNC5=CC=CC6=C5C(=O)N(C6=O)C7CCC(=O)NC7=O
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| InChi Key |
YNGWQHGVASHCBK-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C44H51ClN10O9S/c1-28(2)65(61,62)36-9-4-3-7-33(36)50-40-32(45)26-48-44(52-40)49-29-10-12-30(13-11-29)54-19-17-53(18-20-54)21-23-64-25-24-63-22-16-46-38(57)27-47-34-8-5-6-31-39(34)43(60)55(42(31)59)35-14-15-37(56)51-41(35)58/h3-13,26,28,35,47H,14-25,27H2,1-2H3,(H,46,57)(H,51,56,58)(H2,48,49,50,52)
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| Chemical Name |
N-[2-[2-[2-[4-[4-[[5-chloro-4-(2-propan-2-ylsulfonylanilino)pyrimidin-2-yl]amino]phenyl]piperazin-1-yl]ethoxy]ethoxy]ethyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]acetamide
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| Synonyms |
TL12-186; TL12 186; TL12186
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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 : ~200 mg/mL (~214.72 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5 mg/mL (5.37 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 50.0 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: ≥ 5 mg/mL (5.37 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 50.0 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.0736 mL | 5.3679 mL | 10.7358 mL | |
| 5 mM | 0.2147 mL | 1.0736 mL | 2.1472 mL | |
| 10 mM | 0.1074 mL | 0.5368 mL | 1.0736 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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