AP1903
AP1903 (CAS 195514-63-7) is a synthetic homodimer of an FKBP-binding ligand, engineered to specifically bind and modulate proteins fused to FKBP domains. By inducing controlled dimerization of FKBP fusion proteins, AP1903 functions as a chemical inducer of signal transduction pathways. In fluorescence polarization assays, AP1903 inhibits the mutant F36V-FKBP with an IC50 of 5 nM. In engineered HT1080 human fibrosarcoma cells, AP1903 induces apoptosis via FKBP fusion protein activation, showing an EC50 of approximately 0.1 nM. Its application in vivo has been demonstrated in mouse models engineered for conditional cell ablation, where administration of AP1903 produced a dose-dependent reduction of targeted cell populations (EC50: 0.4 mg/kg). AP1903 is used extensively in biomedical research to study controlled protein activation and apoptosis pathways.
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.
- 1. Audrey M. Goldfarb, Nanda K. Sasi, et al. "Tetrameric TRF2 forms t-loop to protect telomeres from ATM signaling and cNHEJ." bioRxiv. June 28, 2024.
- 2. Sarah M Roelle, Nisha D Kamath, et al. "Mammalian Genomic Manipulation with Orthogonal Bxb1 DNA Recombinase Sites for the Functional Characterization of Protein Variants." ACS Synth Biol. 2023 Nov 17;12(11):3352-3365. PMID: 37922210
- 3. Regina J Lin, Janette Sutton, et al. "Constitutive Turbodomains enhance expansion and antitumor activity of allogeneic BCMA CAR T cells in preclinical models." Sci Adv. 2023 Aug 4;9(31):eadg8694. PMID: 37540748
- 4. Ariana Ghez Farrell, Bernadeta Dadonaite, et al. "Receptor-Binding Domain (RBD) Antibodies Contribute More to SARS-CoV-2 Neutralization When Target Cells Express High Levels of ACE2." bioRxiv. 2022 Aug 30;2022.08.29.505713. PMID: 36093349
- 5. Nidhi Shukla, Sarah M. Roelle, et al. "Mutants of human ACE2 differentially promote SARS-CoV and SARS-CoV-2 spike mediated infection." PLoS Pathog. 2021 Jul 16;17(7):e1009715. PMID: 34270613
- 6. Peng-Chieh Chen, Ya-Wen Hsueh, et al. "FGF primes angioblast formation by inducing ETV2 and LMO2 via FGFR1/BRAF/MEK/ERK." Cell Mol Life Sci 2020 Sep 10. PMID: 32910224
| Physical Appearance | A solid |
| Storage | Store at -20°C |
| M.Wt | 1411.63 |
| Cas No. | 195514-63-7 |
| Formula | C78H98N4O20 |
| Solubility | ≥23.53 mg/mL in DMSO; insoluble in H2O; ≥56.2 mg/mL in EtOH |
| SDF | Download SDF |
| Canonical SMILES | O=C([C@@H](C(C=C1OC)=CC(OC)=C1OC)CC)N2[C@H](C(O[C@@H](C3=CC=CC(OCC(NCCNC(COC4=CC([C@H](CCC(C=C5OC)=CC=C5OC)OC([C@H]6N(C([C@@H](C(C=C7OC)=CC(OC)=C7OC)CC)=O)CCCC6)=O)=CC=C4)=O)=O)=C3)CCC(C=C8)=CC(OC)=C8OC)=O)CCCC2 |
| Shipping Condition | Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice. |
| General tips | We do not recommend long-term storage for the solution, please use it up soon. |
| Kinase experiment [1]: | |
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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]: | |
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Cell lines |
Cloned HT1080 cell lines (ATCC CCL-121) |
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Preparation method |
Limited solubility. General tips for obtaining a higher concentration: Please warm the tube at 37°C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20°C for several months. |
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Reaction Conditions |
37°C |
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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]: | |
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Animal models |
Male nu/nu mice |
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Dosage form |
intravenous injection at 0.01-100 mg/kg |
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Preparation method |
Formulated in [50% N,N-dimethylacetamide/50% (90% PEG-400/10% Tween 80)] at 2 ml/kg |
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Applications |
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. |
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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. |
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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 |
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Quality Control & MSDS
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