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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.
| Targets |
BRD4BD1 (DC50/5h = 500 nM)[1]; DC50: half-maximal degradation concentration, at the half-maximal degradation concentration that degrades 50% of the target protein.
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| ln Vitro |
We found that dBET6 (DC50/5h ~ 10 nM, with DC50/5h referring to half-maximal degradation after 5 hours of treatment), dBET23 (DC50/5h ~ 50 nM) and dBET70 (DC50/5h ~ 5 nM) exhibit the most potent effects on BRD4BD1 protein levels, followed by dBET1 (8) (DC50/5h ~ 500 nM) and dBET57 (DC50/5h ~ 500 nM) (Fig. 3a and Supplementary Fig. 4). For BRD4BD2, dBET70 (DC50/5h ~ 5 nM) has the most pronounced effects, followed by dBET6 (DC50/5h ~ 50 nM), dBET23 (DC50/5h > 1 μM) and dBET1 (DC50/5h ~ 1 μM). dBET57 , which exhibits significant degradation of BRD4BD1, is inactive on BRD4BD2 (Fig. 3b and Supplementary Fig. 4). The cellular activity is thus largely proportional to the observed cooperativity factors (Supplementary Fig. 3), and dBET57 was found remarkably selective for BRD4BD1 in biochemical and cellular assays (Fig. 2e and Fig. 3a, b).[1]
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| Enzyme Assay |
We also note that molecules with short linkers, such as dBET57, would not be able to dimerize CRBN and BRD4 in the conformation observed in the CRBN-dBET23-BRD4BD1 structure since a minimum of 8 carbons would be required to bridge the E3-moeity with the target-moiety and dBET57 comprises a 2-carbon linker (Supplementary Fig. 5c). We therefore asked whether degrader molecules incompatible with the observed binding mode, such as dBET57 or dBET1, would bind in a different overall conformation.
To explore potential differences in binding, we conducted mutational analysis. A set of single amino acid point mutations was introduced in CRBN and BRD4BD1 to obtain a mutational signature of binding. These CRBN mutations were previously shown to bind thalidomide with comparable affinities, except for the IMiD-binding deficient (IBD) control (CRBNP353G W386A)17. When comparing the mutational signatures of different degraders, we find that while dBET6 and 23 share similar profiles (Fig. 4a – c and Supplementary Fig. 2 and and5),5), the mutational signatures of dBET1 and dBET57 are distinct (Fig. 4d – f and Supplementary Fig. 5), consistent with distinct binding surfaces of dBET6/23 and dBET57 (Fig. 4b, e). This suggests that different degrader molecules – depending on linker length and linkage position – result in distinct binding conformations of CRBN-BRD4 complex formation.
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| References | |
| Additional Infomation |
Heterobifunctional small-molecule degraders that induce protein degradation via ligase-mediated ubiquitination show great potential as novel drug therapies. However, our current understanding of the molecular mechanisms underlying target recruitment and selectivity is lacking, which is crucial for the rational design of degraders. This paper utilizes a comprehensive characterization of the ligand-dependent CRBN/BRD4 interaction to demonstrate the plasticity of binding between proteins that do not evolve to form an interaction. Multiple X-ray crystal structures reveal that this plasticity leads to several distinct low-energy binding conformations that can be selectively bound by ligands. We demonstrate that computational protein-protein docking can reveal potential protein-protein interactions and guide the design of a BRD4 selective degrader capable of distinguishing highly homologous BET bromide domains. We find that the plastic contact between proteins confers ligand-induced protein dimerization selectivity, providing a conceptual framework for the development of heterobifunctional ligands. [1]
PROTACs or heterobifunctional degradative molecules (hereinafter referred to as degradative agents) typically contain an E3 ligase-binding scaffold (hereinafter referred to as the E3 moiety), usually a ligand of a thalidomide analog or von Hippel-Lindau tumor suppressor protein (VHL), which is linked to another small molecule (hereinafter referred to as the target moiety) via a linker. The target protein is recruited to the E3 ubiquitin ligase, thereby promoting the ubiquitination and subsequent degradation of the target protein. This principle has been successfully applied to multiple targets, including the bromodomain and terminal extradomain (BET) family (BRD2, BRD3, BRD4), RIPK2, BCR-ABL, FKBP12, BRD9, and ERRα, representing a promising new pharmacological model that is currently being widely explored in the fields of chemical biology and drug discovery. |
| Molecular Formula |
C34H31CLN8O5S
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|---|---|
| Molecular Weight |
699.178544282913
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| Exact Mass |
698.182
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| Elemental Analysis |
C, 58.41; H, 4.47; Cl, 5.07; N, 16.03; O, 11.44; S, 4.59
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| CAS # |
1883863-52-2
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| Related CAS # |
1883863-52-2
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| PubChem CID |
118912822
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| Appearance |
Typically exists as Light yellow to yellow solids at room temperature
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| LogP |
3.7
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
49
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| Complexity |
1380
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC1=C(SC2=C1C(=N[C@H](C3=NN=C(N32)C)CC(=O)NCCNC4=CC=CC5=C4C(=O)N(C5=O)C6CCC(=O)NC6=O)C7=CC=C(C=C7)Cl)C
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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; dBET57; 1883863-52-2; 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; 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethyl]acetamide; dBET57?; CHEMBL5180012; SCHEMBL17553391; TQP1624; 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.
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