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FT113 is a potent and orally bioavailable fatty acid synthase (FASN) inhibitor, with an IC50 of 213 nM for full-length recombinant human FASN enzyme. In cell-based assay, FT113 blocks FASN activity in BT474 cells (IC50, 90 nM). FT113 shows anti-proliferative activity, and exhibits anti-cancer activity both in vitro and in vivo.
| Targets |
FT113 exhibits anti-proliferative activity with IC50 values of 47 and 26 nM, respectively, against PC3 and MV-411 cells [1].
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| ln Vitro |
FT113 exhibits anti-proliferative activity with IC50 values of 47 and 26 nM, respectively, against PC3 and MV-411 cells [1].
FT113 exhibited potent inhibitory activity against the fatty acid synthase (FASN) enzyme with an IC₅₀ of 213 nM in a biochemical assay using full-length recombinant human FASN. [1] In cellular assays, FT113 demonstrated anti-proliferative activity with an IC₅₀ of 47 nM in PC3 human prostate cancer cells cultured in lipid-reduced serum (LRS) medium. [1] FT113 inhibited FASN activity in BT474 human breast cancer cells as measured by the ¹⁴C-acetate incorporation assay, with an IC₅₀ of 90 nM. [1] FT113 also showed anti-proliferative activity against MV-411 human acute myeloid leukemia cells with an IC₅₀ of 26 nM. [1] The compound showed excellent microsomal stability, with 100% remaining after a 30-minute incubation in mouse liver microsomes. [1] The kinetic solubility of FT113 at pH 7.4 was 39 µM. [1] The calculated logP (clogP) was 1.3, and the lipophilic efficiency (LipE) was 5.4. [1] |
| ln Vivo |
In mice and simulators, the oral bioavailability of FT113 (5 mg/kg, mouse) is 95% and 84%, respectively [1]. In mice, FT113 (5, 25, or 50 mg/kg, po, twice daily for 16 days) increases the concentration of malonyl-CoA in tumors and dose-couples tumor growth inhibition [1].
In an MV-411 human cancer cell line mouse xenograft model, oral administration of FT113 at 5, 25, and 50 mg/kg twice daily for 16 days resulted in a dose-dependent increase in tumor malonyl-CoA levels, a substrate of FASN, indicating target engagement and inhibition of FASN activity within the tumor tissue. [1] Treatment with FT113 at 25 and 50 mg/kg (b.i.d.) for 16 days achieved 32% and 50% tumor growth inhibition, respectively, compared to the vehicle control group. [1] |
| Enzyme Assay |
The biochemical potency of compounds against FASN was measured using a CPM (7-diethylamino-3-(4'-maleimidyl-phenyl)-4-methylcoumarin) assay with full-length recombinant human FASN enzyme. The assay measures the production of coenzyme A (CoA) by detecting the formation of a fluorescent CPM-CoA conjugate. [1]
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| Cell Assay |
Anti-proliferative activity was assessed in PC3 human prostate cancer cells. Cells were maintained in growth media supplemented with 10% lipid-reduced serum (LRS), a condition under which PC3 cell growth is dependent on de novo lipogenesis (DNL). Cell viability/proliferation was measured in the presence of the FASN inhibitor. [1]
FASN enzymatic activity in a cellular context was measured using a ¹⁴C-acetate incorporation assay in BT474 human breast cancer cells. This assay measures the conversion of ¹⁴C-acetate to ¹⁴C-acetyl-CoA and its subsequent incorporation into newly synthesized radiolabeled palmitate by cellular FASN. Inhibition of this process reflects cellular FASN inhibition. [1] Anti-proliferative activity was also assessed in MV-411 human acute myeloid leukemia cells. [1] |
| Animal Protocol |
Animal/Disease Models: Athymic nude mice bearing MV-411 cells [1]
Doses: 5, 25, or 50 mg/kg Route of Administration: Orally, twice (two times) daily for 16 days Experimental Results: In mice, 25 mg/kg and 50 mg/kg inhibited tumor growth by 32% and 50%, respectively. Pharmacokinetic Study: FT113 was administered orally to female Balb/c nude mice at a dose of 5 mg/kg. The dosing formulation was a 9:1 (v/v) mixture of PEG400 and ethanol. Blood samples were collected at various time points to determine plasma concentration-time profiles. [1] Pharmacokinetic Study: FT113 was administered orally to male Sprague-Dawley rats at a dose of 5 mg/kg. The dosing formulation was a 9:1 (v/v) mixture of PEG400 and ethanol. Blood samples were collected to determine plasma concentration-time profiles. [1] Efficacy Study (Xenograft Model): Athymic nude mice bearing subcutaneous MV-411 human cancer cell line xenografts were used. When tumor volumes reached 130–140 mm³, mice were randomized into groups (n=4 per group). Mice received vehicle (9:1 PEG400/ethanol) or FT113 at 5, 25, or 50 mg/kg, administered orally twice daily (b.i.d.) for 16 days. Tumors were harvested 4 hours after the last dose for biomarker (malonyl-CoA) analysis. Tumor volumes were also monitored to assess growth inhibition. [1] |
| ADME/Pharmacokinetics |
In female Balb/c nude mice, after a single oral administration of 5 mg/kg FT113, the peak plasma concentration (Cmax) reached 8.4 µM at 2 hours (tmax). The area under the plasma concentration-time curve (AUC₀₋₈h) from 0 to 8 hours was 46 µM·h. The oral bioavailability was 95%. [1] In male Sprague-Dawley rats, after a single oral administration of 5 mg/kg FT113, the peak plasma concentration (Cmax) reached 33 µM at 3 hours (tmax). The AUC₀₋₈h was 440 µM·h. The oral bioavailability was 84%. [1]
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| Toxicity/Toxicokinetics |
FT113 did not show acute toxicity when administered orally to mice at a dose of 5 mg/kg, while its 5-fluorobenzoxazole analogue (compound 27) was not tolerated at the same dose. This suggests that blocking the 6-position of the benzoxazole ring may mitigate potential toxicity by preventing the formation of the active metabolite. [1]
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| References | |
| Additional Infomation |
FT113 is a novel piperazine fatty acid synthase (FASN) inhibitor, a key enzyme in the de novo lipid synthesis pathway that is upregulated in various cancers. [1]
The design of this compound is based on structure-activity relationship (SAR) studies and the co-crystal structure of a related analog (compound 22) bound to the FASN KR domain. The structure reveals key hydrogen bond interactions between FT113 and Ser2021, Gln2031 and Tyr2034, as well as π interactions between the cyclopropyl group and the NADPH cofactor. [1] FT113 has a 6-fluorobenzoxazole group attached to the right side of the piperazine core and a 1-hydroxycyclopropane-1-carboxamide group attached to the left side. The 6-fluoro substitution is crucial for improving tolerability. [1] The synthetic route of FT113 is shown in Figure 1. Starting with methyl 4-(chlorocarbonyl)benzoate and 2-amino-5-fluorophenol, the synthesis proceeds through condensation, saponification, amide coupling, deprotection, and final amide coupling steps. [1] This compound is used as a tool molecule to validate the concept of FASN inhibition in a DNL-driven disease model. [1] |
| Molecular Formula |
C22H20FN3O4
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| Molecular Weight |
409.410308837891
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| Exact Mass |
409.143
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| CAS # |
1630808-89-7
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| PubChem CID |
118621601
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| Appearance |
White to off-white solid powder
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| LogP |
1.9
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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 |
30
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| Complexity |
671
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC1C=CC2=C(C=1)OC(C1C=CC(=CC=1)C(N1CCN(CC1)C(C1(CC1)O)=O)=O)=N2
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| InChi Key |
DSTWHRGOCUOKDE-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H20FN3O4/c23-16-5-6-17-18(13-16)30-19(24-17)14-1-3-15(4-2-14)20(27)25-9-11-26(12-10-25)21(28)22(29)7-8-22/h1-6,13,29H,7-12H2
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| Chemical Name |
[4-(6-fluoro-1,3-benzoxazol-2-yl)phenyl]-[4-(1-hydroxycyclopropanecarbonyl)piperazin-1-yl]methanone
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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 : ~62.5 mg/mL (~152.66 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.08 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 (5.08 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 | 2.4425 mL | 12.2127 mL | 24.4254 mL | |
| 5 mM | 0.4885 mL | 2.4425 mL | 4.8851 mL | |
| 10 mM | 0.2443 mL | 1.2213 mL | 2.4425 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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