Size | Price | Stock | Qty |
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500μg |
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1mg |
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5mg |
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10mg |
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25mg |
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50mg |
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100mg |
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Other Sizes |
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Purity: ≥98%
SP-13786 (UAMC-1110, FAP-IN-1) is a novel, potent and highly selective inhibitor of fibroblast activation protein (FAP) with IC50 of 3.2 nM; it also inhibits prolyl oligopeptidase (PREP) with an IC50 of 1.8 μM. Fibroblast activation protein (FAP) is a serine protease related to dipeptidyl peptidase IV (DPPIV). It has been convincingly linked to multiple disease states involving remodeling of the extracellular matrix. FAP inhibition is investigated as a therapeutic option for several of these diseases, with most attention so far devoted to oncology applications. The log D values, plasma stabilities, and microsomal stabilities of SP-13786 were found to be highly satisfactory. Pharmacokinetic evaluation in mice of SP-13786 demonstrated high oral bioavailability, plasma half-life, and the potential to selectively and completely inhibit FAP in vivo.
Targets |
FAP (IC50 = 3.2 nM); PREP (IC50 = 1.8 μM)
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ln Vitro |
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ln Vivo |
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Enzyme Assay |
Reversibility of the Probes Based on a Dialysis Experiment[2]
Recombinant human FAP (rhFAP) was incubated for 15 min at 37°C with a concentration of probe that was predicted to inhibit around 90% of FAP’s activity (5: 1.08 nM; 6: 2.50 nM; 7: 1.35 nM; UAMC1110: 0.77 nM diluted in FAP assay buffer: 50 mM Tris-HCl pH 8.0, 140 mM NaCl, and 1 mg/ml BSA). As a solvent control, rhFAP was incubated with 0.0002% DMSO. After 15 min of incubation, FAP activity was determined as published by Bracke et al. (2019). Subsequently, the samples were dialyzed at 4°C against FAP assay buffer (using a 10 kDa cut-off Slide-A-Lyzer MINI dialysis device. Buffer (14 ml) was exchanged after 3 h, 6 h, 24 h, 3 days, and 7 days, and after each of these time points, a FAP activity measurement was performed. For the UAMC1110 parent compound, FAP activity was only measured on days 3 and 7. |
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Cell Assay |
Fibroblast activation protein (FAP) is a proline-selective protease that belongs to the S9 family of serine proteases. It is typically highly expressed in the tumor microenvironment (TME) and especially in cancer-associated fibroblasts, the main cell components of the tumor stroma. The exact role of its enzymatic activity in the TME remains largely unknown. Hence, tools that enable selective, activity-based visualization of FAP within the TME can help to unravel FAP's function. We describe the synthesis, biochemical characterization, and application of three different activity-based probes (biotin-, Cy3-, and Cy5-labeled) based on the FAP-inhibitor UAMC1110, an in-house developed molecule considered to be the most potent and selective FAP inhibitor available. We demonstrate that the three probes have subnanomolar FAP affinity and pronounced selectivity with respect to the related S9 family members. Furthermore, we report that the fluorescent Cy3- and Cy5-labeled probes are capable of selectively detecting FAP in a cellular context, making these chemical probes highly suitable for further biological studies. Moreover, proof of concept is provided for in situ FAP activity staining in patient-derived cryosections of urothelial tumors.Front Chem. 2021 Apr 14;9:640566.
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Animal Protocol |
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ADME/Pharmacokinetics |
Oral bioavailalbility in rats = 51%
T1/2 = 3.2 hrs |
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References | |||
Additional Infomation |
Fibroblast activation protein (FAP) is a serine protease related to dipeptidyl peptidase IV (DPPIV). It has been convincingly linked to multiple disease states involving remodeling of the extracellular matrix. FAP inhibition is investigated as a therapeutic option for several of these diseases, with most attention so far devoted to oncology applications. We previously discovered the N-4-quinolinoyl-Gly-(2S)-cyanoPro scaffold as a possible entry to highly potent and selective FAP inhibitors. In the present study, we explore in detail the structure-activity relationship around this core scaffold. We report extensively optimized compounds that display low nanomolar inhibitory potency and high selectivity against the related dipeptidyl peptidases (DPPs) DPPIV, DPP9, DPPII, and prolyl oligopeptidase (PREP). The log D values, plasma stabilities, and microsomal stabilities of selected compounds were found to be highly satisfactory. Pharmacokinetic evaluation in mice of selected inhibitors demonstrated high oral bioavailability, plasma half-life, and the potential to selectively and completely inhibit FAP in vivo.[1]
Fibroblast activation protein (FAP) is a proline-selective protease that belongs to the S9 family of serine proteases. It is typically highly expressed in the tumor microenvironment (TME) and especially in cancer-associated fibroblasts, the main cell components of the tumor stroma. The exact role of its enzymatic activity in the TME remains largely unknown. Hence, tools that enable selective, activity-based visualization of FAP within the TME can help to unravel FAP's function. We describe the synthesis, biochemical characterization, and application of three different activity-based probes (biotin-, Cy3-, and Cy5-labeled) based on the FAP-inhibitor UAMC1110, an in-house developed molecule considered to be the most potent and selective FAP inhibitor available. We demonstrate that the three probes have subnanomolar FAP affinity and pronounced selectivity with respect to the related S9 family members. Furthermore, we report that the fluorescent Cy3- and Cy5-labeled probes are capable of selectively detecting FAP in a cellular context, making these chemical probes highly suitable for further biological studies. Moreover, proof of concept is provided for in situ FAP activity staining in patient-derived cryosections of urothelial tumors.[2] |
Molecular Formula |
C₁₇H₁₄F₂N₄O₂
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Molecular Weight |
344.32
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Exact Mass |
344.108
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Elemental Analysis |
C, 59.30; H, 4.10; F, 11.04; N, 16.27; O, 9.29
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CAS # |
1448440-52-5
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Related CAS # |
1448440-52-5;
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PubChem CID |
71621488
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Appearance |
Typically exists as White to off-white solid at room temperature
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Density |
1.4±0.1 g/cm3
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Boiling Point |
676.4±55.0 °C at 760 mmHg
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Flash Point |
362.9±31.5 °C
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Vapour Pressure |
0.0±2.1 mmHg at 25°C
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Index of Refraction |
1.621
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LogP |
0.22
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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 |
25
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Complexity |
588
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Defined Atom Stereocenter Count |
1
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SMILES |
FC1(CN(C(CNC(C2C=CN=C3C=CC=CC=23)=O)=O)[C@H](C#N)C1)F
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InChi Key |
PUOOCZVRHBHJRS-NSHDSACASA-N
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InChi Code |
InChI=1S/C17H14F2N4O2/c18-17(19)7-11(8-20)23(10-17)15(24)9-22-16(25)13-5-6-21-14-4-2-1-3-12(13)14/h1-6,11H,7,9-10H2,(H,22,25)/t11-/m0/s1
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Chemical Name |
N-[2-[(2S)-2-cyano-4,4-difluoropyrrolidin-1-yl]-2-oxoethyl]quinoline-4-carboxamide
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Synonyms |
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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 |
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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) |
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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
Injection Formulation 1: DMSO : Tween 80: Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *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). View More
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)] 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). View More
Oral Formulation 3: Dissolved in PEG400  (Please use freshly prepared in vivo formulations for optimal results.) |
Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 2.9043 mL | 14.5214 mL | 29.0428 mL | |
5 mM | 0.5809 mL | 2.9043 mL | 5.8086 mL | |
10 mM | 0.2904 mL | 1.4521 mL | 2.9043 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.
Abstract Image J Med Chem.2014 Apr 10;57(7):3053-74. td> |