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Purity: ≥98%
dBET57 is a novel BRD4 heterobifunctional small-molecule ligand (PROTAC) which exhibits significant and selective degradation of BRD4 BD1 but is inactive on BRD4 BD2.
Molecular Formula |
C34H31CLN8O5S
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Molecular Weight |
699.18
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Exact Mass |
698.1827
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CAS # |
1883863-52-2
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Related CAS # |
1883863-52-2
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Appearance |
Typically exists as solids (or liquids in special cases) at room temperature
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SMILES |
O=C(NCCNC1=CC=CC(C(N2C(CC3)C(NC3=O)=O)=O)=C1C2=O)C[C@H]4C5=NN=C(C)N5C6=C(C(C)=C(C)S6)C(C7=CC=C(Cl)C=C7)=N4
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InChi Key |
CZRLOIDJCMKJHE-UXMRNZNESA-N
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InChi Code |
InChI=1S/C34H31ClN8O5S/c1-16-17(2)49-34-27(16)29(19-7-9-20(35)10-8-19)38-23(30-41-40-18(3)42(30)34)15-26(45)37-14-13-36-22-6-4-5-21-28(22)33(48)43(32(21)47)24-11-12-25(44)39-31(24)46/h4-10,23-24,36H,11-15H2,1-3H3,(H,37,45)(H,39,44,46)/t23-,24?/m0/s1
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Chemical Name |
2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)acetamide
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Synonyms |
dBET57 dBET-57 dBET 57
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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 Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
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 : ~250 mg/mL (~357.56 mM)
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Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (2.97 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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.  (Please use freshly prepared in vivo formulations for optimal results.) |
Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 1.4302 mL | 7.1512 mL | 14.3025 mL | |
5 mM | 0.2860 mL | 1.4302 mL | 2.8605 mL | |
10 mM | 0.1430 mL | 0.7151 mL | 1.4302 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.
Structure of the DDB1ΔB-CRBN-dBET23-BRD4BD1 complex (a) The chemical structure of dBET23 is depicted with the target-moiety in red, the linker in black and cyan, and the E3-moiety in blue. (b) Cartoon representation of DDB1ΔB-CRBN-dBET23-BRD4BD1: DDB1 highlighting domains BPA (red), BPC (orange) and DDB1-CTD (grey); CRBN with domains NTD (blue), HBD (cyan) and CTD (green); BRD4BD1 (magenta). The Zn2+-ion is drawn as a grey sphere and dBET23 as sticks representation in yellow. The FO-FC map is shown as green mesh for dBET23 contoured at 3.0σ. (c) Superposition of DDB1ΔB-CRBN-dBET23-BRD4BD1 with CRBN bound to lenalidomide (pdb: 4tz4) and BRD4BD1 bound to JQ1-(S) (pdb: 3mxf). Surface representation for CRBN and BRD4BD1 are shown in gray and magenta, respectively. dBET23 is shown in yellow, JQ1 in green, and thalidomide in cyan. (d) Side-chain interactions between BRD4BD1, CRBN, and dBET23. Residues of BRD4BD1 mutated in this study are highlighted in cyan. Nat Chem Biol . 2018 Jul;14(7):706-714. td> |
Plasticity of CRBN-substrate interactions (a) TR-FRET. dBET23 titrated to BRD4BD1-SPYCATCHER-BODIPY, Terbium-antiHis antibody and various His6-DDB1ΔB-CRBN wild type and His6-DDB1-CRBN mutant proteins. The mean peak heights for dose response curves of three independent replicates are shown as dot-plot. TR-FRET data in this figure is presented as means ± s.d. (b) surface representation of CRBN highlighting the residues involved in dBET23 mediated BRD4BD1 binding in orange (residues Y59, L60, Q86, Q100, F102, H103, P104, D149, F150, G151, I152, I154, K156, P352, H353, E377, H378). CRBN interface residues mutated for biochemical assays are indicated. (c) TR-FRET. dBET23 titrated to DDB1ΔB-CRBNSPYCATCHER-BODIPY, Terbium-Streptavidin and various BRD4BD1-biotin wild type and mutant proteins. The mean peak heights for dose response curves of three independent replicates are shown as dot-plot. TR-FRET data in this figure is presented as means ± s.d. (d) as in a but titrating dBET57. (e) surface representation of CRBN highlighting the BRD4BD1 interacting residues for the dBET57 mediated recruitment in orange (residues: Q325, H353, Y355, H357, I371, G372, R373, E377, V388, Q390, C394, A395, S396, H397, T418, S420). CRBN interface residues mutated for biochemical assays are indicated. (f) as in b but titrating dBET57. (g) Cartoon representation of DDB1ΔB-CRBN-dBET57-BRD4BD1: DDB1 highlighting domains BPA (red), BPC (orange) and DDB1-CTD (grey); CRBN with domains NTD (blue), HBD (cyan) and CTD (green); BRD4BD1 (magenta). The Zn2+-ion is drawn as a grey sphere. dBET57 was not modelled in this structure but instead superpositions of lenalidomide (from pdb: 5fqd) and JQ1 (from pdb: 3mxf) are shown in yellow sticks. (h) Superposition of CRBN and BRD4BD1 for the dBET23 and dBET57 containing complexes. Superposition was carried out over the CRBN-CTD (residues 320 – 400). (i) The chemical structures of dBET57 is depicted with the target-moiety in red, the linker in black and cyan, and the E3-moiety in blue. Nat Chem Biol . 2018 Jul;14(7):706-714. td> |
Degrader mediated BRD4 recruitment is governed by negative cooperativity (a) TR-FRET. dBET23 titrated to DDB1ΔB-CRBNSPY-BODIPY, Terbium-Streptavidin and various BRD4BD1-biotin wild type and mutant proteins. The mean peak heights for dose response curves of three independent replicates are shown as dot-plot. Data in this figure is presented as means ± s.d. (n=3). (b) Competitive binding assay for dBET1 binding to DDB1ΔB-CRBN. Increasing concentrations of dBET1 titrated to preformed DDB1ΔB-CRBN-lenalidomideAtto565 complex in presence or absence of BRD4BD1 or BRD4BD2. (c) As in b but using dBET6, (d) dBET23, or (e) dBET57. All data in this figure are independent replicates presented as means ± s.d. (n=3). Nat Chem Biol . 2018 Jul;14(7):706-714. td> |