| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
| Targets |
Signal Transducer and Activator of Transcription 3 (STAT3) [1]
|
|---|---|
| ln Vitro |
KT-333 is a potent and selective degrader of STAT3, with DC50 values ranging from 2.5 to 11.8 nM in four anaplastic large cell lymphoma (ALCL) cell lines. [1]
In human peripheral blood mononuclear cells (PBMCs), mass spectrometry demonstrated selective degradation of STAT3 over nearly 9000 proteins, including other STAT family members. [1] Treatment with KT-333 led to rapid apoptosis of ALK+ ALCL cells (which express NPM-ALK fusion oncoproteins and are dependent on STAT3 signaling). [1] Time-course transcriptomic and proteomic analyses in SU-DHL-1 cells showed time-dependent changes: significant STAT3 depletion was observed at 8 hours; modulation of canonical STAT3 downstream genes (including SOCS3, IL-2RA, and GRZMB) was observed at 24 hours; pathways including interferon response and cell cycle were significantly enriched at 48 hours. A high correlation was observed between the transcriptomic and proteomic datasets. [1] Preclinical in vitro experiments demonstrated that approximately 90% degradation of STAT3 for 48 hours was sufficient to drive ALK+ ALCL lines into irreversible cell growth inhibition and death. [1] KT-333 ammonium (11.8±2.3 nM, 48 h) caused irreversible growth inhibition of the SU-DHL-1 cell line after degradation of STAT3 and induced caspase 3/7 activity, a hallmark of apoptosis[1]. KT-333 ammonium showed degradation of STAT3 protein, and in cell phenotypic analysis, the GI50 values ranged from 8.1 to 57.4 nM against multiple ALCL cell lines[1]. |
| ln Vivo |
In vivo xenograft studies using SU-DHL-1 and SUP-M2 ALCL models demonstrated dose-dependent tumor growth suppression following KT-333 treatment. [1]
A PK-PD-efficacy analysis in the SU-DHL-1 xenograft model showed that tumor regression could be achieved with intermittent dosing schedules that achieved 90% degradation of STAT3 for about 48 hours over a weekly or bi-weekly dosing interval. [1] KT-333 ammonium (5, 10, 15 and 45 mg/kg, iv.; once a week for two weeks) showed dose-dependent antitumor activity. Mice dosed at 5 mg/kg achieved 79.9% tumor growth inhibition (TGI), while mice dosed at 10, 15 or 45 mg/kg achieved complete tumor regression, and these effects lasted until the end of the study [1]. KT-333 ammonium (10, 20 and 30 mg/kg, iv.; once a week for two weeks) showed dose-dependent antitumor activity. Mice dosed at 10 mg/kg achieved 83.8% tumor growth inhibition (TGI), while mice dosed at 20 or 30 mg/kg achieved complete tumor regression, and these effects lasted until the end of the study [1]. |
| Cell Assay |
The DC50 (concentration for 50% degradation) of KT-333 was determined in four anaplastic large cell lymphoma (ALCL) lines, yielding values of 2.5 - 11.8 nM. [1]
To understand cellular responses, time-course transcriptomic and proteomic analyses were performed using SU-DHL-1 cells treated with KT-333. Time-dependent changes in both mRNA and protein levels of STAT3-regulated genes and pathways were observed. [1] The correlation between transcriptomic and proteomic data sets was assessed by comparing changes in mRNA and protein levels of bona fide STAT3 regulated targets. [1] In vitro experiments were conducted to determine the required level of STAT3 degradation for irreversible cell growth inhibition. It was found that maintaining approximately 90% degradation for 48 hours was sufficient to drive ALK+ ALCL lines into irreversible cell growth inhibition and death. [1] |
| Animal Protocol |
In vivo xenograft studies were performed using SU-DHL-1 and SUP-M2 ALCL models to evaluate tumor growth suppression. [1]
An indirect response model was established to describe the relationship between exposure and target degradation in the tumor. Consistent with in vitro data, PK-PD-efficacy analysis in the SU-DHL-1 xenograft model showed that tumor regression could be achieved with intermittent dosing schedules that achieved 90% degradation of STAT3 for about 48 hours over a weekly or bi-weekly dosing interval. [1] |
| ADME/Pharmacokinetics |
KT-333 exhibits high solubility in PBS buffer (103 mg/mL, pH 7.4). [1]
It has low to moderate clearance in rat, dog, and monkey, and moderate plasma half-lives across pre-clinical species. [1] Based on preclinical ADME and PK/PD/efficacy relationship, KT-333 is predicted to drive tumor regression using weekly doses. [1] |
| References | |
| Additional Infomation |
STAT3 has been historically considered "undruggable". Heterobifunctional degraders represent a novel therapeutic modality. [1]
KT-333 is a first-in-class, potent and selective STAT3 degrader being developed for the treatment of hematologic malignancies and solid tumors. [1] KT-333 is a small molecule targeted protein degrader discovered by iterative medicinal chemistry SAR. [1] Aberrant activation of STAT3 is observed in many cancers including lymphomas and leukemias. [1] KT-333 can be administered parenterally in the clinic on an intermittent dosing regimen predicted to be both efficacious and tolerated in STAT3-dependent hematologic malignancies. [1] |
| Molecular Formula |
C60H77CLN11O14PS
|
|---|---|
| Molecular Weight |
1274.81
|
| Exact Mass |
1273.479832
|
| CAS # |
2839758-34-6
|
| Related CAS # |
2839758-34-6; 2502186-80-1; 2502186-79-8
|
| PubChem CID |
172395678
|
| Appearance |
White to off-white solid at room temperature
|
| Hydrogen Bond Donor Count |
9
|
| Hydrogen Bond Acceptor Count |
16
|
| Rotatable Bond Count |
23
|
| Heavy Atom Count |
88
|
| Complexity |
2550
|
| Defined Atom Stereocenter Count |
8
|
| SMILES |
CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCC4=C(C(=CC=C4)OC[C@H](CCC(=O)N)NC(=O)[C@@H]5CC[C@H]6N5C(=O)[C@H](CN(CC6)C(=O)C)NC(=O)C7=CC8=C(N7)C=CC(=C8)C(=O)P(=O)(O)[O-])Cl)O.[NH4+]
|
| InChi Key |
JIYKXEYTTBFNJP-BGVAWFLRSA-N
|
| InChi Code |
InChI=1S/C60H74ClN10O14PS.H3N/c1-32(35-13-15-37(16-14-35)52-33(2)63-31-87-52)64-56(78)47-27-42(73)28-70(47)58(80)53(60(4,5)6)68-50(75)12-8-10-36-9-7-11-48(51(36)61)85-30-40(18-22-49(62)74)65-55(77)46-21-19-41-23-24-69(34(3)72)29-45(57(79)71(41)46)67-54(76)44-26-39-25-38(17-20-43(39)66-44)59(81)86(82,83)84;/h7,9,11,13-17,20,25-26,31-32,40-42,45-47,53,66,73H,8,10,12,18-19,21-24,27-30H2,1-6H3,(H2,62,74)(H,64,78)(H,65,77)(H,67,76)(H,68,75)(H2,82,83,84);1H3/t32-,40-,41+,42+,45-,46-,47-,53+;/m0./s1
|
| Chemical Name |
azanium [2-[[(5S,8S,10aR)-3-acetyl-8-[[(2S)-5-amino-1-[2-chloro-3-[4-[[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]amino]-4-oxobutyl]phenoxy]-5-oxopentan-2-yl]carbamoyl]-6-oxo-1,2,4,5,8,9,10,10a-octahydropyrrolo[1,2-a][1,5]diazocin-5-yl]carbamoyl]-1H-indole-5-carbonyl]-hydroxyphosphinate
|
| Synonyms |
KT-333 ammonium; KT-333 ammonium; Lirodegimod (KT 333); KT333 ammonium
|
| 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 |
| 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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
|
|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.7844 mL | 3.9222 mL | 7.8443 mL | |
| 5 mM | 0.1569 mL | 0.7844 mL | 1.5689 mL | |
| 10 mM | 0.0784 mL | 0.3922 mL | 0.7844 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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