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AP1903

Homodimer binding to FKBP CAS# 195514-63-7

AP1903

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Chemical structure

AP1903

3D structure

Chemical Properties of AP1903

Cas No. 195514-63-7 SDF Download SDF
PubChem ID 16135625 Appearance Powder
Formula C78H98N4O20 M.Wt 1411.63
Type of Compound N/A Storage Desiccate at -20°C
Synonyms Rimiducid
Solubility DMSO : 50 mg/mL (35.42 mM; Need ultrasonic)
Chemical Name [(1R)-3-(3,4-dimethoxyphenyl)-1-[3-[2-[2-[[2-[3-[(1R)-3-(3,4-dimethoxyphenyl)-1-[(2S)-1-[(2S)-2-(3,4,5-trimethoxyphenyl)butanoyl]piperidine-2-carbonyl]oxypropyl]phenoxy]acetyl]amino]ethylamino]-2-oxoethoxy]phenyl]propyl] (2S)-1-[(2S)-2-(3,4,5-trimethoxyphenyl)butanoyl]piperidine-2-carboxylate
SMILES CCC(C1=CC(=C(C(=C1)OC)OC)OC)C(=O)N2CCCCC2C(=O)OC(CCC3=CC(=C(C=C3)OC)OC)C4=CC(=CC=C4)OCC(=O)NCCNC(=O)COC5=CC=CC(=C5)C(CCC6=CC(=C(C=C6)OC)OC)OC(=O)C7CCCCN7C(=O)C(CC)C8=CC(=C(C(=C8)OC)OC)OC
Standard InChIKey GQLCLPLEEOUJQC-ZTQDTCGGSA-N
Standard InChI InChI=1S/C78H98N4O20/c1-13-57(53-43-67(93-7)73(97-11)68(44-53)94-8)75(85)81-37-17-15-25-59(81)77(87)101-61(31-27-49-29-33-63(89-3)65(39-49)91-5)51-21-19-23-55(41-51)99-47-71(83)79-35-36-80-72(84)48-100-56-24-20-22-52(42-56)62(32-28-50-30-34-64(90-4)66(40-50)92-6)102-78(88)60-26-16-18-38-82(60)76(86)58(14-2)54-45-69(95-9)74(98-12)70(46-54)96-10/h19-24,29-30,33-34,39-46,57-62H,13-18,25-28,31-32,35-38,47-48H2,1-12H3,(H,79,83)(H,80,84)/t57-,58-,59-,60-,61+,62+/m0/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of AP1903

DescriptionAP1903 is a homodimer binding to FKBP, elicits potent and dose-dependent apoptotic death of engineered cell line HT1080 in culture with an EC50 of 0.1 nM. AP1903 induces Fas activation. Fas receptor also known as tumor necrosis factor receptor superfamily member 6 (TNFRSF6).In Vitro:The human fibrosarcoma line HT1080 is engineered to express stably a fusion protein comprising a myristoylation sequence, two copies of F36V-FKBP, and the human first apoptosis signal (Fas) intracellular domain. AP1903 elicits potent and dose-dependent apoptotic death of these engineered cells in culture, with an EC50 of ≈0.1 nM[1]. Maximal killing occurred in the presence of 3 to 10 nM AP1903, and the IC50 is approximately 0.2 nM. LV′VFas-transduced T lymphocytes expressing high levels of CD25 (top panel) are eliminated by with 66%±7.5% (n=10) efficiency. When cells are examined after CD25 expression returned to basal levels, 63%±4.7% (n=9) killing is observed after AP1903 treatment[2].In Vivo:AP1903 (i.v.,0.01, 0.1, 1, 10, and 100 mg/kg) elicits a dose-dependent decrease in serum hGH levels, with a half-maximal effective dose of 0.4±0.1 mg/kg[1].

References:
[1]. Clackson T, et al. Redesigning an FKBP-ligand interface to generate chemical dimerizers with novel specificity. Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10437-42. [2]. Thomis DC, et al. A Fas-based suicide switch in human T cells for the treatment of graft-versus-host disease. Blood. 2001 Mar 1;97(5):1249-57. [3]. Valamehr, Bahram, et al. GENOMIC ENGINEERING OF PLURIPOTENT CELLS. Patent. US20180155717A1.

Protocol

Kinase experiment [1]:

FKBP Binding Assay

Subsaturating concentrations of protein were incubated for 30 min with 2.5 nM fluoro-FK506 and serial dilutions of competitor ligand in the wells of a Dynatech microfluor plate. Polarization was read on a Jolley FPM-2 (Jolley Consulting and Research, Grayslake, IL). The increase in polarization on binding was used as a direct readout of percentage of bound probe, compared with controls containing no competitor (100%) or no protein (0%). The concentration of competitor resulting in a 50% probe displacement (IC50) was determined by a nonlinear least square fit by using the four-parameter algorithm.

Cell experiment [1]:

Cell lines

Cloned HT1080 cell lines (ATCC CCL-121)

Preparation method

Limited solubility. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

37oC

Applications

The human fibrosarcoma line HT1080 was engineered to express stably a fusion protein comprising a myristoylation sequence, two copies of F36V-FKBP, and the human Fas intracellular domain. AP1903 elicits potent and dose-dependent apoptotic death of these engineered cells in culture, with an EC50 of ≈0.1 nM.

Animal experiment [1]:

Animal models

Male nu/nu mice

Dosage form

intravenous injection at 0.01-100 mg/kg

Preparation method

Formulated in [50% N,N-dimethylacetamide/50% (90% PEG-400/10% Tween 80)] at 2 ml/kg

Application

Male nu/nu mice were injected with HT1080 cell line expressing a Fas-F36V-FKBP construct that also constitutively secretes hGH. AP1903 exhibits a dose-dependent decrease in serum hGH levels, with a half-maximal effective dose of 0.4 ± 0.1 mg/kg.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

1. Clackson T, Yang W, Rozamus LW et al. Redesigning an FKBP-ligand interface to generate chemical dimerizers with novel specificity. Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10437-42

AP1903 Dilution Calculator

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AP1903 Molarity Calculator

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Preparing Stock Solutions of AP1903

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 0.7084 mL 3.542 mL 7.084 mL 14.168 mL 17.71 mL
5 mM 0.1417 mL 0.7084 mL 1.4168 mL 2.8336 mL 3.542 mL
10 mM 0.0708 mL 0.3542 mL 0.7084 mL 1.4168 mL 1.771 mL
50 mM 0.0142 mL 0.0708 mL 0.1417 mL 0.2834 mL 0.3542 mL
100 mM 0.0071 mL 0.0354 mL 0.0708 mL 0.1417 mL 0.1771 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on AP1903

IC50: 5 nM for F36V-FKBP in competition fluorescence polarization assay

FKBP ligand homodimers can be used to trigger signaling events inside cells and animals that have been engineered to express fusions between and FKBP appropriate signaling domains. However, use of these dimerizers in vivo is potentially limited by ligand binding to endogenous FKBP. AP1903 is a homodimer of the modified ligand for FKBP.

In vitro: By selective inhibition of FKBP, AP1903 elicited potent and dose-dependent apoptotic death of the human fibrosarcoma line HT1080 engineered cells in culture, with an EC50 of ~0.1 nM [1].

In vivo: In an mouse model of conditional cell ablation, animals were i.v. treated with various doses of AP1903, and then serum hGH levels were determined as a measure of the number of surviving cells. Results showed that AP1903 elicited a dose-dependent decrease in levels of serum hGH, with a half-maximal effective dose of 0.4 mg/kg [1].

Clinical trials: In an intravenous, single-blind, placebo- and saline-controlled, ascending-dose study, AP1903 was shown to be safe and well tolerated at all dose levels and demonstrated a favorable PK profile at doses well above the anticipated therapeutic dose [2].

References:
[1] Clackson T, Yang W, Rozamus LW, Hatada M, Amara JF, Rollins CT, Stevenson LF, Magari SR, Wood SA, Courage NL, Lu X, Cerasoli F Jr, Gilman M, Holt DA.  Redesigning an FKBP-ligand interface to generate chemical dimerizers with novel specificity. Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10437-42.
[2] Iuliucci JD, Oliver SD, Morley S, Ward C, Ward J, Dalgarno D, Clackson T, Berger HJ.   Intravenous safety and pharmacokinetics of a novel dimerizer drug, AP1903, in healthy volunteers. J Clin Pharmacol. 2001 Aug;41(8):870-9.

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References on AP1903

Intravenous safety and pharmacokinetics of a novel dimerizer drug, AP1903, in healthy volunteers.[Pubmed:11504275]

J Clin Pharmacol. 2001 Aug;41(8):870-9.

AP1903 is a novel gene-targeted drug that is being developed for use in drug-regulated cell therapies. An intravenous, single-blind, placebo- and saline-controlled, ascending-dose study was performed to evaluate the safety, tolerability, and pharmacokinetics of AP1903. Twenty-eight normal healthy male volunteers were randomized into five dosage groups of AP1903 (0.01, 0.05, 0.1, 0.5, and 1 mg/kg). Within each group, 4 volunteers received a single dose of AP1903, 1 volunteer received an equal volume of placebo, and 1 received an equal volume of normal saline. The only exception was in the 0.5 mg/kg group, in which 4 volunteers were dosed: 3 received AP1903 and 1 received normal saline. All dosages were administered as intravenous infusions over 2 hours. Clinical safety parameters were monitored, and serial blood and urine samples were collected for analysis of AP1903. No drug-related adverse events were observed at any of the dose levels with the possible exception of facial flushing in 1 volunteer at the 1.0 mg/kg dose level. AP1903 plasma levels were directly proportional to the administered dose, with mean Cmax values ranging from approximately 10 to 1,275 ng/mL over the 0.01 to 1.0 mg/kg dose range. Following the infusion period, blood concentrations revealed a rapid distribution phase, with plasma levels being reduced to approximately 18%, 7%, and 1% of the maximal concentration at 0.5, 2, and 10 hours postdose, respectively. AP1903 was shown to be safe and well tolerated at all dose levels and demonstrated a favorable pharmacokinetic profile at doses well above the anticipated therapeutic dose.

Description

Rimiducid (AP1903) is a dimerizer agent that acts by cross-linking the FKBP domains. Rimiducid (AP1903) dimerizes the Caspase 9 suicide switch and rapidly induces apoptosis.

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