SK-575 is a PROTAC degrader of PARP1 with anticancer activity. SK-575 potently inhibits the growth of cancer cells bearing BRCA1/2 mutations and induces potent and specific degradation of PARP1 in various human cancer cells even at low picomolar concentrations. SK-575 achieves durable tumor growth inhibition in mice when used as a single agent or in combination with cytotoxic agents, such as temozolomide and cisplatin. These data demonstrate that SK-575 is a highly potent and efficacious PARP1 degrader.
Physicochemical Properties
| Molecular Formula | C47H53FN8O8 |
| Molecular Weight | 876.97093462944 |
| Exact Mass | 876.397 |
| CAS # | 2523016-96-6 |
| PubChem CID | 162664494 |
| Appearance | Light yellow to yellow solid powder |
| LogP | 5 |
| Hydrogen Bond Donor Count | 4 |
| Hydrogen Bond Acceptor Count | 11 |
| Rotatable Bond Count | 19 |
| Heavy Atom Count | 64 |
| Complexity | 1770 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | O=C1N(C2CCC(=O)NC2=O)C(=O)C2=CC=CC(NCCNC(=O)CCCCCCCCCCC(N3CCN(C(C4C(=CC=C(CC5=NNC(=O)C6=CC=CC=C56)C=4)F)=O)CC3)=O)=C12 |
| InChi Key | HPBWDZVXFSTVMR-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C47H53FN8O8/c48-35-19-18-30(29-37-31-12-9-10-13-32(31)43(60)53-52-37)28-34(35)45(62)55-26-24-54(25-27-55)41(59)17-8-6-4-2-1-3-5-7-16-39(57)50-23-22-49-36-15-11-14-33-42(36)47(64)56(46(33)63)38-20-21-40(58)51-44(38)61/h9-15,18-19,28,38,49H,1-8,16-17,20-27,29H2,(H,50,57)(H,53,60)(H,51,58,61) |
| Chemical Name | N-[2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethyl]-12-[4-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]piperazin-1-yl]-12-oxododecanamide |
| 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: 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) |
Biological Activity
| ln Vitro | In MDA-MB-436 and Capan-1 cells, SK-575 suppresses cell growth with IC50 values of 19 ± 6 nM and 56 ± 12 nM, respectively[1]. Good PARP1 degradation activity is demonstrated by SK-575 (0-1 μM, 24 h) in cancer cell lines (MDA-MB-436, Capan-1, and SW620 cells)[1]. SK-575 (0-10 μM, 24 h) efficiently and dose-dependently stimulates the production of γH2AX in MDA-MB-436 and Capan-1 cells[1]. |
| ln Vivo | In an HR-deficient xenograft model, SK-575 (25 and 50 mg/kg, intraperitoneally once daily for 5 days) dramatically suppressed tumor development as a single drug [1]. SK-575 (intraperitoneally, once day for five days; 25 mg/kg). injection, single) substantially induced PARP1 degradation in SW620 xenograft tissue, with effects lasting longer than 24 hours, and completely exposed tumors for more than 24 hours in a vehicle [1]. |
| Cell Assay |
Western Blot Analysis[1] Cell Types: MDA-MB-436, Capan-1 and SW620 cells Tested Concentrations: 10000, 1000, 300, 100, 30, 10, 3, 1, 0.3, in a dose-dependent manner[1]. , 0.1, 0.03 and 0.01 nM Incubation Duration: 24 hrs (hours) Experimental Results: demonstrated good PARP1 degradation activity in these cancer cell lines (MDA-MB-436, Capan-1 and SW620 cells) with IC50 values of 1.26, 6.72 and 0.509 respectively nM. Effectively induces γH2AX formation in MDA-MB-436 and Capan-1 cells in a dose-dependent manner. |
| Animal Protocol |
Animal/Disease Models: Male BALB/c nude mice (bearing xenografted Capan- 1 tumor) [1] Doses: 25 mg/kg, 50 mg/kg Route of Administration: IP, one time/day for 5 days Experimental Results: Inhibition of tumor growth . These doses (25 and 50 mg/kg) of SK-575 were well tolerated, with no mouse deaths or significant weight loss observed during treatment. Animal/Disease Models: Female ICR mice (20-23 g, 6-7 weeks old, n=3 per group) [1] Doses: 25 mg/kg Route of Administration: intraperitoneal (ip) injection, single dose (pharmacokinetic/PK/PK analysis) Experimental Results: pharmacokinetic/PK/PK parameters of SK-575 in female ICR mice[1]. Parameter mean Tmax (h) 0.25 Cmax (ng/mL) 1843 AUCall (ng/mL*h) 5316 AUCinf (ng/mL*h) 5363 t1/2 (ng/mL) 3.08 |
| References |
[1]. Discovery of SK-575 as a Highly Potent and Efficacious Proteolysis-Targeting Chimera Degrader of PARP1 for Treating Cancers. J Med Chem. 2020 Oct 8;63(19):11012-11033. |
Solubility Data
| Solubility (In Vitro) | DMSO : ~100 mg/mL (~114.03 mM) |
| 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 (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *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). 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)] *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. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL 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). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.1403 mL | 5.7014 mL | 11.4029 mL | |
| 5 mM | 0.2281 mL | 1.1403 mL | 2.2806 mL | |
| 10 mM | 0.1140 mL | 0.5701 mL | 1.1403 mL |