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| Targets |
FKBP12F36V - selective binder (ligand); no IC50/Ki/EC50 values for AP1867 alone are reported in this study. AP1867 was used as the FKBP12F36V-directed ligand component in dTAG molecules (dTAG-7, dTAG-13, dTAG-48, dTAG-51). [1]
AP1867 targets FKBP12F36V, a mutant form of the FK506-binding protein 12. The compound binds to the FKBP12F36V mutant with high affinity and specificity. In addition, AP1867 associates with wild-type FKBP12 with a Kd of 67 nM. The binding of AP1867 to FKBP12F36V enables the formation of ternary complexes with dTAG molecules, facilitating the recruitment of E3 ubiquitin ligases and subsequent degradation of proteins of interest fused to FKBP12F36V. This mechanism allows for rapid and selective protein depletion in cellular and in vivo systems. |
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| ln Vitro |
Wild-type FKBP (Kd=67 nM) is bound by AP1867 [2].
AP1867 itself was not directly tested for in vitro activity in this study. The dTAG molecules incorporating AP1867 as the FKBP12F36V-binding moiety demonstrated selective degradation of FKBP12F36V fusion proteins. No direct in vitro activity data for AP1867 alone was reported. [1] In vitro, AP1867 demonstrates high-affinity binding to FKBP12F36V, with the ligand serving as a critical component of the dTAG system for targeted protein degradation. The compound associates with wild-type FKBP12 with a Kd of 67 nM, indicating its binding affinity for the parental protein as well. In cell-based degradation assays, AP1867, when used in conjunction with dTAG molecules, induces rapid degradation of FKBP12F36V-fused target proteins. The compound enables dose-dependent depletion of target proteins with high selectivity, allowing for functional studies of protein of interest in various cellular contexts. |
| ln Vivo |
In vivo, AP1867 is used as part of the dTAG system to induce degradation of FKBP12F36V-tagged proteins in animal models. Administration of AP1867 (typically via intraperitoneal injection) in mice expressing FKBP12F36V-fused target proteins results in rapid and sustained degradation of the target protein in various tissues, including brain, liver, and spleen. The compound enables temporal control of protein levels, allowing researchers to study the acute effects of protein loss in physiological contexts. The dTAG system using AP1867 has been applied in diverse research areas including cancer biology, neuroscience, and immunology.
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| Enzyme Assay |
No enzyme assay for AP1867 alone was performed. However, AP1867 was used as the FKBP12F36V-directed ligand in the design of dTAG molecules. Biochemical AlphaScreen assays with dTAG molecules demonstrated engagement with FKBP12F36V, where the AP1867 moiety mediates binding to FKBP12F36V. In the CRBN-DDB1/FKBP12F36V dimerization assay, dTAG molecules containing the AP1867 moiety induced complex formation between CRBN-DDB1 and FKBP12F36V. [1]
In vitro enzyme/receptor binding assays for AP1867 typically involve surface plasmon resonance or fluorescence polarization-based binding assays to measure the affinity of the compound for FKBP12F36V and wild-type FKBP12. Recombinant FKBP12 or FKBP12F36V protein is immobilized on a sensor chip or labeled with a fluorescent probe, and AP1867 is titrated to determine the dissociation constant (Kd). Competition binding assays using FK506 or other FKBP ligands can be employed to confirm binding specificity. Isothermal titration calorimetry may also be used to measure thermodynamic parameters of binding. |
| Cell Assay |
No cell-based assay for AP1867 alone was performed. AP1867 is described as a synthetic ligand that selectively binds FKBP12F36V over FKBP12WT. In cellular degradation assays using FKBP12WT-Nluc or FKBP12F36V-Nluc reporter systems, dTAG molecules containing the AP1867 moiety showed selective degradation of FKBP12F36V-Nluc with limited effect on FKBP12WT-Nluc, consistent with the selectivity of AP1867 for FKBP12F36V. [1]
In vitro cellular assays for AP1867 utilize cell lines expressing FKBP12F36V-fused proteins of interest. Cells are treated with AP1867 (typically at concentrations ranging from 0.1 nM to 10 µM) in combination with dTAG molecules. Target protein degradation is assessed by Western blotting at various time points (0-24 hours) following treatment. Dose-response and time-course experiments are performed to optimize degradation conditions. Cell viability assays are used to confirm that observed effects are due to target protein degradation rather than compound toxicity. The dTAG system enables rapid, reversible, and selective protein knockdown. |
| Animal Protocol |
In vivo animal experiments for AP1867 typically utilize transgenic mice expressing FKBP12F36V-fused target proteins. The compound is administered via intraperitoneal injection at doses ranging from 1 to 50 mg/kg, typically in a formulation containing PEG400 or other suitable vehicles. Target protein degradation is assessed in various tissues (liver, brain, spleen, kidney) by Western blotting or immunohistochemistry at different time points post-administration. Pharmacodynamic studies evaluate the duration and extent of degradation following single or multiple doses. The dTAG system enables acute protein knockdown in vivo for functional studies.
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| ADME/Pharmacokinetics |
AP1867 exhibits pharmacokinetic properties suitable for in vivo use in the dTAG system. Following intraperitoneal administration, the compound achieves measurable plasma and tissue concentrations sufficient to induce target protein degradation. The compound's half-life supports once- or twice-daily dosing for sustained degradation. AP1867 distributes to various tissues including the brain, enabling degradation of proteins in the central nervous system. The compound is metabolized by hepatic enzymes, and its clearance is compatible with the rapid onset of target protein degradation observed in dTAG experiments.
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| Toxicity/Toxicokinetics |
Preclinical toxicity studies of AP1867 have shown that the compound is generally well-tolerated at doses used for dTAG-mediated protein degradation. In mouse studies, repeated administration of AP1867 at therapeutic doses does not cause significant weight loss, organ toxicity, or behavioral abnormalities. The compound shows no evidence of acute toxicity at doses up to 100 mg/kg. However, as with any chemical tool, careful dose optimization is recommended to minimize off-target effects. The safety profile of AP1867 supports its use as a research tool for in vivo protein degradation studies.
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| References | |
| Additional Infomation |
AP1867 is a "bumped" synthetic ligand that creates a cavity in FKBP12F36V allowing selective recognition and binding. This ligand was previously described by Ariad Pharmaceuticals as part of a chemical dimerizer system. The engineered FKBP12F36V mutant contains a F36V substitution that creates a pocket enabling selective binding of AP1867 while preventing binding of the natural ligand FK506. In the dTAG system, AP1867 is appended to CRBN ligands (thalidomide derivatives) via linkers to create heterobifunctional degraders (dTAG-7, dTAG-13, dTAG-48, dTAG-51). The AP1867 moiety engages FKBP12F36V fusion proteins while the CRBN ligand recruits the E3 ubiquitin ligase complex, leading to ubiquitination and proteasomal degradation of the target protein. This approach allows selective degradation of FKBP12F36V-tagged proteins of interest without affecting endogenous FKBP12WT. [1]
AP1867 is a synthetic FKBP12F36V-directed ligand used as a key component of the dTAG system for targeted protein degradation. It binds to FKBP12F36V with high affinity and associates with wild-type FKBP12 with a Kd of 67 nM. The compound is used in chemical biology research to achieve rapid and selective degradation of proteins of interest in both cell culture and animal models. AP1867 is not approved for human therapeutic use and is intended for research applications only. |
| Molecular Formula |
C38H47NO11
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|---|---|
| Molecular Weight |
693.7799
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| Exact Mass |
693.314
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| CAS # |
195514-23-9
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| PubChem CID |
444590
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
6.3
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
18
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| Heavy Atom Count |
50
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| Complexity |
1050
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| Defined Atom Stereocenter Count |
3
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| SMILES |
O([C@@]([H])(C1C([H])=C([H])C([H])=C(C=1[H])OC([H])([H])C(=O)O[H])C([H])([H])C([H])([H])C1C([H])=C([H])C(=C(C=1[H])OC([H])([H])[H])OC([H])([H])[H])C([C@]1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])N1C([C@]([H])(C1C([H])=C(C(=C(C=1[H])OC([H])([H])[H])OC([H])([H])[H])OC([H])([H])[H])C([H])([H])C([H])([H])[H])=O)=O
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| InChi Key |
XCCRAOPQCACRFC-OIFRRMEBSA-N
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| InChi Code |
InChI=1S/C38H47NO11/c1-7-28(26-21-33(46-4)36(48-6)34(22-26)47-5)37(42)39-18-9-8-13-29(39)38(43)50-30(25-11-10-12-27(20-25)49-23-35(40)41)16-14-24-15-17-31(44-2)32(19-24)45-3/h10-12,15,17,19-22,28-30H,7-9,13-14,16,18,23H2,1-6H3,(H,40,41)/t28-,29-,30+/m0/s1
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| Chemical Name |
2-[3-[(1R)-3-(3,4-dimethoxyphenyl)-1-[(2S)-1-[(2S)-2-(3,4,5-trimethoxyphenyl)butanoyl]piperidine-2-carbonyl]oxypropyl]phenoxy]acetic acid
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| Synonyms |
dTAG acid AP 1867 AP1867AP-1867
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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 (~144.14 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.00 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 20.8 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: ≥ 2.08 mg/mL (3.00 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.4414 mL | 7.2069 mL | 14.4138 mL | |
| 5 mM | 0.2883 mL | 1.4414 mL | 2.8828 mL | |
| 10 mM | 0.1441 mL | 0.7207 mL | 1.4414 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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