NVP-DKY709 HCl (NVP-DKY-709; DKY-709) is a first-in-class and selective cereblon (CRBN) glue degrader of IKZF2 with anticancer and may be used for cancer immunotherapy. It spares IKZF1 and IKZF3 from degradation. X-ray crystal structure of IKZF2 zinc fingers bound to DDB1:CRBN:NVP-DKY709 explained the target selectivity of NVP-DKY709. In vitro, NVP-DKY709 modulated Treg cell and Teff cell functions. In a mouse breast cancer xenograft model, daily oral dosing with NVP-DKY709 led to degradation of IKZF2 in tumour and peripheral blood Treg cells, reducing tumour growth similarly to that achieved with the anti-PD1 antibody PDR001. Oral NVP-DKY709 effectively degraded IKZF2 in monkeys and patients and is currently being evaluated in a first-in-human phase I trial in solid tumours.
Physicochemical Properties
| Related CAS # | 2291360-73-9 |
| Appearance | Typically exists as solid at room temperature |
| 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) |
Biological Activity
| Targets | IZKF2 (DC50 = 4 nM ) |
| ln Vitro | NVP-DKY709 is a first-in-class and selective cereblon (CRBN) glue degrader of IKZF2, which spares IKZF1 and IKZF3 from degradation. Solving the X-ray crystal structure of IKZF2 zinc fingers bound to DDB1:CRBN:NVP-DKY709 explained the target selectivity of NVP-DKY709. In vitro, NVP-DKY709 modulated Treg cell and Teff cell functions [1]. |
| ln Vivo | In a mouse breast cancer xenograft model, daily oral dosing with NVP-DKY709 led to degradation of IKZF2 in tumour and peripheral blood Treg cells, reducing tumour growth similarly to that achieved with the anti-PD1 antibody PDR001. Oral NVP-DKY709 effectively degraded IKZF2 in monkeys and patients and is currently being evaluated in a first-in-human phase I trial in solid tumours [1]. |
| ADME/Pharmacokinetics | Orally available (F > 35%) |
| References | [1]. Developing an IKZF2 glue degrader. Nat Rev Drug Discov. 2023 Apr;22(4):271. |
| Additional Infomation | Tumours can evade immune system attack through the recruitment of immune-suppressive FOXP3+ regulatory T (Treg) cells, which can limit the activation and expansion of tumour-specific effector T (Teff) cells. Recently, the Ikaros transcription factor family member IKZF2 (Helios) — which plays a crucial role in maintaining the function and stability of Treg cells — has emerged as an attractive target for enhancing the antitumour immune response. However, targeting zinc finger transcription factors such as IKZF2 is challenging, as they are mostly unstructured and lack ligandable sites. |
Solubility Data
| 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 (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.) |