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| Targets |
PDE6D CK1α IKZF1 IKZF3
FPFT-2216 targets multiple proteins for degradation through a molecular glue mechanism. It targets phosphodiesterase 6D (PDE6D), zinc finger transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), and casein kinase 1α (CK1α). FPFT-2216 operates by stabilizing interactions between target proteins and E3 ubiquitin ligases, enabling their efficient removal from the cell through the ubiquitin-proteasome pathway. This molecular glue mechanism allows researchers to explore therapeutic strategies beyond conventional inhibition. |
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| ln Vitro |
In MOLT4 cells, FPFT-2216 (1 μM; 5 hours) not only destroys its known targets, IKZF1, IKZF3, and CK1α, but also PDE6D [1]. PDE6D completely degrades in 2 hours with FPFT-2216 (1 μM; 0 h, 2 h, 4 h, 6 h, 16 h, 24 h), and it continues to degrade in MOLT4 cells for at least 24 hours [1]. PDE6D is more than 50% degraded in FPFT-2216 at a dose of 8 nM, with maximum degradation in MOLT4 cells at 200 nM (0 nM, 1.6 nM, 8 nM, 40 nM, 200 nM, 1 μM; 4 hours). Dosage breaks down PDE6D, IKZF1, IKZF3, and CK1α[1]. The proliferation of MIA PaCa-2 cells that are dependent on KRASG12C is not inhibited by FPFT-2216 [1]. While FPFT-2216 (10, 20, 40 μM; 14 or 24 hours) significantly upregulates IL-2, in naive CD4+ T cells it is less efficacious than Pomalidomide [2]. The immunomodulatory drugs (IMiD) ubiquitin-proteasome degradation substrates IKZF1 and CK-1α are degraded by FPFT-2216 (10 μM; 14 or 24 hours) in naive CD4+ T cells [2].
In vitro, FPFT-2216 (1 μM; 5 hours) in MOLT4 cells degrades its known targets IKZF1, IKZF3, CK1α, and PDE6D. PDE6D completely degrades within 2 hours with FPFT-2216 at 1 μM and continues to degrade for at least 24 hours. FPFT-2216 exhibits stronger inhibitory effects on human lymphoma cell proliferation than known thalidomide derivatives and induces upregulation of p53 and its transcriptional targets. It shows the strongest cell growth inhibitory activity (0.02 μM) among a series of analogs. FPFT-2216 largely suppresses DLBCL cell line proliferation in a concentration-dependent manner, reducing cell viability to ≤50% in five of eight cell lines. |
| ln Vivo |
In CRBNI391V mice, FPFT-2216 (30 mg/kg; po or ip) significantly degrades CK-1α and IKZF1 [2].
In vivo, FPFT-2216 demonstrates potent antitumor activity. In lymphoma models, FPFT-2216 activates p53, inhibits NFκB signaling via CK1α degradation, and shows potent antitumor efficacy. FPFT-2216 (30 mg/kg; p.o. or i.p.) induces significant degradation of CK1α and IKZF1 in CRBN[391V mice. Administered orally once daily for five consecutive days per week for 3-4 weeks, FPFT-2216 enhances p53 stabilization and the tumor growth-inhibitory activities of MDM2 inhibitors against hematopoietic malignant cell lines. As a single agent, FPFT-2216 induces rapid and near-complete tumor regression in a patient-derived xenograft (PDX) model of DLBCL. |
| Enzyme Assay |
The in vitro protein degradation assay for FPFT-2216 is conducted in MOLT4 cells. Cells are treated with FPFT-2216 at 1 μM for varying time points (0, 2, 4, 6, 16, 24 hours). Target protein levels (IKZF1, IKZF3, CK1α, PDE6D) are measured by Western blotting. Cell proliferation is assessed in DLBCL cell lines using standard cell viability assays such as CellTiter-Glo. IC₅₀ values are calculated from dose-response curves. The compound's effects on p53 and its transcriptional targets are evaluated by Western blotting and qPCR.
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| Cell Assay |
Western Blot Analysis[1]
Cell Types: MOLT4 cells Tested Concentrations: 1 μM Incubation Duration: 0 h, 2 h, 4 h, 6 h, 16 h, 24 h Experimental Results: demonstrated complete degradation of PDE6D within 2 h, and the degradation of PDE6D persisted for at least 24 h. Western Blot Analysis[1] Cell Types: MOLT4 cells Tested Concentrations: 0 nM, 1.6 nM, 8 nM, 40 nM, 200 nM, 1 μM Incubation Duration: 4 h Experimental Results: demonstrated over 50% degradation of PDE6D at a dose of 8 nM, while maximum degradation of PDE6D along with IKZF1, IKZF3, and CK1α at a dose of 200 nM. Cellular assays for FPFT-2216 are conducted in MOLT4 cells and various lymphoma cell lines including DLBCL cell lines. Cells are treated with FPFT-2216 at concentrations ranging from nanomolar to micromolar. Protein degradation is assessed by Western blotting for IKZF1, IKZF3, CK1α, and PDE6D. Cell proliferation and viability are measured using standard assays such as CellTiter-Glo. The compound's effects on p53 pathway are evaluated by measuring p53 protein levels and expression of its transcriptional targets. NFκB signaling is assessed by measuring relevant downstream targets. |
| Animal Protocol |
Animal/Disease Models: CRBNI391V mice[2]
Doses: 30 mg/kg (solubilized in 0.5% carboxymethylcellulose/sodium and 0.25% Tween 80) Route of Administration: po or ip Experimental Results: Induced significant degradation of CK-1α, and IKZF1. In vivo studies for FPFT-2216 are conducted in mouse models of lymphoma and other hematopoietic malignancies. The compound is administered orally once daily for five consecutive days per week for 3-4 weeks. Doses of 30 mg/kg are used for oral or intraperitoneal administration. Efficacy is assessed by measuring tumor growth inhibition, time to endpoint, and tumor regression. Pharmacodynamic markers such as CK1α, IKZF1, and IKZF3 degradation are measured in tumor tissues by Western blotting. Combination studies with MDM2 inhibitors or rituximab are performed to assess synergistic effects. |
| ADME/Pharmacokinetics |
FPFT-2216 is orally bioavailable with favorable pharmacokinetic properties. It has a molecular weight of 292.31 g/mol and a molecular formula of C₁₂H₁₂N₄O₃S. The compound is administered orally in vivo at 30 mg/kg. Storage conditions: powder at -20°C. As a small molecule molecular glue, it is expected to have good oral absorption. Detailed PK parameters such as half-life and bioavailability are not extensively reported in the available literature for this research compound.
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| Toxicity/Toxicokinetics |
Toxicity data for FPFT-2216 is derived from in vivo studies in mouse models. In lymphoma models, the compound was tolerated at the studied doses. As with all research compounds, FPFT-2216 is intended for research use only and not for human therapeutic applications. The compound's mechanism as a protein degrader may have distinct toxicity profiles compared to traditional inhibitors. Comprehensive toxicology studies would be required for clinical development.
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| References | |
| Additional Infomation |
FPFT-2216 is a "molecular glue" compound that induces targeted protein degradation of PDE6D, IKZF1, IKZF3, and CK1α. It is a thalidomide derivative cereblon modulator. In MOLT4 cells, FPFT-2216 at 1 μM completely degrades PDE6D within 2 hours. In vivo, FPFT-2216 (30 mg/kg) induces significant degradation of CK1α and IKZF1 and shows potent antitumor efficacy in lymphoma PDX models. It has a molecular formula of C₁₂H₁₂N₄O₃S and a molecular weight of 292.31 g/mol. FPFT-2216 is a valuable research tool for studying targeted protein degradation and cancer therapeutics.
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| Molecular Formula |
C12H12N4O3S
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|---|---|
| Molecular Weight |
292.31
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| Exact Mass |
292.063
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| CAS # |
2367619-87-0
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| PubChem CID |
151861511
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| Appearance |
Light yellow to light brown solid powder
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| LogP |
0.3
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
20
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| Complexity |
408
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| Defined Atom Stereocenter Count |
0
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| SMILES |
N1C(=O)CCC(N2C=C(C3C(OC)=CSC=3)N=N2)C1=O
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| InChi Key |
SKUSCUALKIOIST-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C12H12N4O3S/c1-19-10-6-20-5-7(10)8-4-16(15-14-8)9-2-3-11(17)13-12(9)18/h4-6,9H,2-3H2,1H3,(H,13,17,18)
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| Chemical Name |
3-[4-(4-methoxythiophen-3-yl)triazol-1-yl]piperidine-2,6-dione
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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 |
| 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 : 100 mg/mL (342.10 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (8.55 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 25.0 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: ≥ 2.5 mg/mL (8.55 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 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. View More
Solubility in Formulation 3: 2.5 mg/mL (8.55 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.4210 mL | 17.1051 mL | 34.2103 mL | |
| 5 mM | 0.6842 mL | 3.4210 mL | 6.8421 mL | |
| 10 mM | 0.3421 mL | 1.7105 mL | 3.4210 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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