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Purity: ≥98%
SD-36 is a novel, potent and highly efficacious STAT3 degrader based on PROTAC technology with a Kd of ~50 nM, demonstrating high selectivity over other STAT family members and in vivo antitumor activity. SD-36 also effectively degrades mutated STAT3 proteins in cells and suppresses the transcriptional activity of STAT3 (IC50=10 nM). SD-36 exerts robust anti-tumor activity, and achieves complete and long-lasting tumor regression in mouse tumor models. SD-36 is composed of the STAT3 inhibitor SI-109, a linker, and an analog of CRBN ligand Lenalidomide for E3 ubiquitin ligase.
| Targets |
CRBN; STAT3; SD-36 is a PROTAC (PROteolysis TArgeting Chimera) that selectively degrades STAT3 (Signal Transducer and Activator of Transcription 3) via the ubiquitin-proteasome system. It binds to the SH2 domain of STAT3 and recruits the CRBN (Cereblon) E3 ligase, leading to STAT3 ubiquitination and degradation. No direct IC50/Ki values for STAT3 binding were reported in the study.[1]
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| ln Vitro |
By inducing cell cycle arrest and/or apoptosis, SD-36 inhibits the growth of acute myeloid leukemia and anaplastic large cell lymphoma cell lines [1]. In MOLM-16, DEL, Karpas-299, KI-JK, SU-DHL-I, and SUP-M2 cell lines, SD-36 (0.005-5 μM; 4 days) exhibits potent activity (IC50<2 μM). In MOLM-16 cells, SD-36 (1 μM; 5 hours) completely depletes monomeric and dimeric STAT3 protein [1].
- SD-36 induced STAT3 degradation in multiple leukemia and lymphoma cell lines (e.g., Karpas-299, SU-DHL-1, MOLM-16) with DC50 (degradation concentration 50%) values ranging from 10–100 nM. - It showed high selectivity for STAT3 over other STAT family members (STAT1, STAT2, STAT4, STAT5A/B, STAT6). - In Karpas-299 (ALCL) and SU-DHL-1 (DLBCL) cells, SD-36 (100 nM) induced G1 cell-cycle arrest and apoptosis (measured by Annexin V/PI staining). - Western blot analysis confirmed near-complete STAT3 degradation within 4–8 hours of treatment, with no effect on STAT1 or STAT5. - RNA-seq analysis revealed suppression of STAT3-regulated genes (e.g., MYC, BCL2, CCND1). - Clonogenic assays demonstrated that SD-36 (100 nM) significantly reduced colony formation in STAT3-dependent cell lines.[1] |
| ln Vivo |
SD-36 (25-100 mg/kg; intravenously; administered weekly for 4 weeks) achieves full and persistent tumor remission in rats [1]. ?SD-36 successfully suppressed tumor growth when treated at 25 and 50 mg/kg on days 1, 3, and 5 per week, and was obtained at 100 mg/kg using the same regimen in an SU-DHL-1 xenograft model Complete tumor remission [1]. ?SD-36 50 mg/kg three times a week completely suppresses tumor growth in the SUP-M2 tumor model [1].
- SD-36 induced STAT3 degradation in multiple leukemia and lymphoma cell lines (e.g., Karpas-299, SU-DHL-1, MOLM-16) with DC50 (degradation concentration 50%) values ranging from 10–100 nM. - It showed high selectivity for STAT3 over other STAT family members (STAT1, STAT2, STAT4, STAT5A/B, STAT6). - In Karpas-299 (ALCL) and SU-DHL-1 (DLBCL) cells, SD-36 (100 nM) induced G1 cell-cycle arrest and apoptosis (measured by Annexin V/PI staining). - Western blot analysis confirmed near-complete STAT3 degradation within 4–8 hours of treatment, with no effect on STAT1 or STAT5. - RNA-seq analysis revealed suppression of STAT3-regulated genes (e.g., MYC, BCL2, CCND1). - Clonogenic assays demonstrated that SD-36 (100 nM) significantly reduced colony formation in STAT3-dependent cell lines.[1] |
| Enzyme Assay |
- SPR (Surface Plasmon Resonance) was used to measure binding affinity between SD-36 and STAT3’s SH2 domain. The compound showed high-affinity binding (no exact KD reported).
- Ubiquitination assays confirmed that SD-36 promotes STAT3 polyubiquitination in a CRBN-dependent manner.[1] |
| Cell Assay |
Cell Viability Assay[1]
Cell Types: MOLM-16, DEL, Karpas-299, KI-JK, SU-DHL-I, SUP-M2 Cell line Tested Concentrations: 0.005, 0.05, 0.5, 5 μM Incubation Duration: 4 days Experimental Results: Exhibits potent activity (IC50<2 μM) in these cell lines. Western Blot Analysis[1] Cell Types: MOLM-16 Cell Tested Concentrations: 1 μM Incubation Duration: 5 hrs (hours) Experimental Results: Complete depletion of monomeric and dimeric STAT3 protein. - Cell viability assays (CellTiter-Glo): SD-36 inhibited growth in STAT3-dependent cell lines (e.g., Karpas-299, SU-DHL-1) with GI50 values of ~50–100 nM. - Western blotting: Cells were treated with SD-36 (10–1000 nM) for 24h, lysed, and probed for STAT3, p-STAT3, and downstream targets (e.g., c-Myc, Bcl-2). - Flow cytometry: Annexin V/PI staining was performed after 48h treatment to assess apoptosis. - qRT-PCR: STAT3 target gene expression (MYC, BCL2, CCND1) was quantified after 24h treatment.[1] |
| Animal Protocol |
Animal/Disease Models: SCID female mouse (MOLM-16 xenograft model) [1]
Doses: 25, 50, 100 mg/kg Route of Administration: intravenous (iv) (iv)injection; weekly dosing for 4 weeks Experimental Results: weekly dosing 25 and 50 mg/kg for 4 weeks, can effectively inhibit tumor growth. Complete tumor regression was induced at 100 mg/kg weekly or 50 mg/kg twice weekly for 4 weeks. - Xenograft models: Mice were implanted with Karpas-299 or SU-DHL-1 cells (5×10^6 cells/mouse, subcutaneous). - Dosing: SD-36 was dissolved in 10% DMSO + 40% PEG300 + 50% saline and administered intraperitoneally (IP) at 25 mg/kg, once daily (QD) for 21 days. - Tumor measurement: Tumor volume was monitored 3x/week via calipers. - Tissue collection: Tumors and major organs were harvested for IHC, Western blot, and H&E staining.[1] |
| ADME/Pharmacokinetics |
Plasma exposure: After a single 25 mg/kg IP dose, SD-36 showed Cmax = ~5 µM and t1/2 = ~4–6 h in mice.
- Tumor penetration: Tumor/plasma ratio was ~0.5–1.0, indicating moderate distribution. |
| Toxicity/Toxicokinetics |
Plasma exposure: After a single 25 mg/kg IP dose, SD-36 showed Cmax = ~5 µM and t1/2 = ~4–6 h in mice.
- Tumor penetration: Tumor/plasma ratio was ~0.5–1.0, indicating moderate distribution. |
| References | |
| Additional Infomation |
- SD-36 is the first STAT3-targeting PROTAC to achieve complete tumor regression in vivo.
- It overcomes limitations of traditional STAT3 inhibitors by inducing complete protein degradation rather than just inhibition. - Potential therapeutic applications: T-cell lymphomas, DLBCL, and STAT3-driven solid tumors.[1] Signal transducer and activator of transcription 3 (STAT3) is an attractive cancer therapeutic target. Here we report the discovery of SD-36, a small-molecule degrader of STAT3. SD-36 potently induces the degradation of STAT3 protein in vitro and in vivo and demonstrates high selectivity over other STAT members. Induced degradation of STAT3 results in a strong suppression of its transcription network in leukemia and lymphoma cells. SD-36 inhibits the growth of a subset of acute myeloid leukemia and anaplastic large-cell lymphoma cell lines by inducing cell-cycle arrest and/or apoptosis. SD-36 achieves complete and long-lasting tumor regression in multiple xenograft mouse models at well-tolerated dose schedules. Degradation of STAT3 protein, therefore, is a promising cancer therapeutic strategy. |
| Molecular Formula |
C59H62F2N9O12P
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|---|---|
| Molecular Weight |
1158.14726209641
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| Exact Mass |
1157.422
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| Elemental Analysis |
C, 61.19; H, 5.40; F, 3.28; N, 10.88; O, 16.58; P, 2.67
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| CAS # |
2429877-44-9
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| Related CAS # |
SD-36 sodium;2429877-44-9 (free acid);
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| PubChem CID |
156588550
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| Appearance |
White to off-white solid powder
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| LogP |
3.2
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| Hydrogen Bond Donor Count |
8
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| Hydrogen Bond Acceptor Count |
14
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| Rotatable Bond Count |
20
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| Heavy Atom Count |
83
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| Complexity |
2550
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| Defined Atom Stereocenter Count |
4
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| SMILES |
P(C1C=CC(=CC=1)C(C1C=CC=CC=1)NC([C@H](CCC(N)=O)NC([C@@H]1CC[C@@H]2CCN(C(CCCCCC#CC3=CC=CC4C(N(CC=43)C3C(NC(CC3)=O)=O)=O)=O)C[C@@H](C(N21)=O)NC(C1=CC2C=C(C(F)F)C=CC=2N1)=O)=O)=O)(=O)(O)O
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| InChi Key |
JKCSCHXVWPSGBG-OPKPGBGESA-N
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| InChi Code |
InChI=1S/C59H62F2N9O12P/c60-59(61,83(80,81)82)39-21-23-43-38(31-39)32-45(63-43)54(75)65-46-34-68(51(73)20-11-3-1-2-6-13-35-18-12-19-41-42(35)33-69(57(41)78)47-26-28-50(72)66-55(47)76)30-29-40-22-25-48(70(40)58(46)79)56(77)64-44(24-27-49(62)71)53(74)67-52(36-14-7-4-8-15-36)37-16-9-5-10-17-37/h4-5,7-10,12,14-19,21,23,31-32,40,44,46-48,52,63H,1-3,11,20,22,24-30,33-34H2,(H2,62,71)(H,64,77)(H,65,75)(H,67,74)(H,66,72,76)(H2,80,81,82)/t40-,44+,46+,47?,48+/m1/s1
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| Chemical Name |
((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(benzhydrylamino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-ynoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)-1H-indol-5-yl)difluoromethyl)phosphonic
acid
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| Synonyms |
SD36; SD 36; P-[[2-[[[(5S,8S,10aR)-8-[[[(1S)-4-amino-1-[[(diphenylmethyl)amino]carbonyl]-4-oxobutyl]amino]carbonyl]-3-[8-[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1-oxo-1H-isoindol-4-yl]-1-oxo-7-octyn-1-yl]decahydro-6-oxopyrrolo[1,2-a][1,5]diazocin-5-yl]amino]carbonyl]-1H-indol-5-yl]difluoromethyl]phosphonic acid; 2429877-44-9; [4-[[[(2S)-2-[[(5S,8S,10aR)-5-[[5-(difluoromethyl)-1H-indole-2-carbonyl]amino]-3-[8-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-4-yl]oct-7-ynoyl]-6-oxo-1,2,4,5,8,9,10,10a-octahydropyrrolo[1,2-a][1,5]diazocine-8-carbonyl]amino]-5-amino-5-oxopentanoyl]amino]-phenylmethyl]phenyl]phosphonic acid; SD-36
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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. |
| 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 (~43.17 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.25 mg/mL (1.08 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 12.5 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: ≥ 1.25 mg/mL (1.08 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 12.5 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: ≥ 1.25 mg/mL (1.08 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 | 0.8634 mL | 4.3172 mL | 8.6345 mL | |
| 5 mM | 0.1727 mL | 0.8634 mL | 1.7269 mL | |
| 10 mM | 0.0863 mL | 0.4317 mL | 0.8634 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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