PROTAC CBP/p300/BRD4 Degrader-1
PROTAC CBP/p300/BRD4 Degrader-1 is a dual-target PROTAC degrader with DC50 values of 8.8 pM (BRD4), 6.55 nM (CBP), and 1.05 nM (p300). PROTAC CBP/p300/BRD4 Degrader-1 induces CRBN- and proteasome-dependent degradation of BRD4 and CBP/p300, downregulates c-Myc and acetyl-H3K27, induces apoptosis. PROTAC CBP/p300/BRD4 Degrader-1 acts as an antiproliferative and antitumor agent, induces tumor growth inhibition in xenograft models. PROTAC CBP/p300/BRD4 Degrader-1 can be used for the research of prostate cancer and colorectal cancer.
(Pink: BRD4 (BD1) and BRD4 (BD2) and CBP and p300 ligand (HY-181759); Blue: Cereblon ligand (HY-14658); Black: linker).
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- CAS No.: 3109024-12-3
- Formule: C41H42F3N7O7
- Masse moléculaire:801.81
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Stockage:
Please store the product under the recommended conditions in the Certificate of Analysis.
To place orders, for customer services and technical support, please contact: MedChemExpress USA
Tel: 609-228-6898 E-mail: [email protected] [email protected]
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Activité biologique
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Chemical Information
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Activité biologique
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BRD4 8.8 pM (DC50) |
CBP 6.55 nM (DC50) |
p300 1.05 nM (DC50) |
BRD4 BD1 44.6 nM (IC50) |
BRD4 BD2 13.1 nM (IC50) |
CBP 110.8 nM (IC50) |
p300 102.6 nM (IC50) |
PROTAC CBP/p300/BRD4 Degrader-1 (29c) exhibits potent antiproliferative activity against PC-3 cells (IC50=2.80 nM), DU145 cells (IC50=6.62 nM), 22Rv1 cells (IC50=16.02 nM) and RM-1 cells (IC50=145.00 nM); it shows low cytotoxicity against normal human prostate epithelial RWPE-1 cells (IC50=4.38 μM) with a selectivity index (SI) > 1500 for PC-3/RWPE-1 and > 600 for DU145/RWPE-1, and exhibits nanomolar antiproliferative activity against various colorectal cancer cell lines[1].
PROTAC CBP/p300/BRD4 Degrader-1 (30 min-2 h) exhibits inhibitory activity against BRD4 (BD1), BRD4 (BD2), p300 and CBP in in vitro biochemical assays, with IC50 values of 44.6 nM, 13.1 nM, 102.6 nM and 110.8 nM, respectively[1].
PROTAC CBP/p300/BRD4 Degrader-1 binds strongly to CRBN with a Kd value of 3.24 μM[1].
PROTAC CBP/p300/BRD4 Degrader-1 (24 h, 48 h, 72 h, 96 h) displays time-dependent antiproliferative activity against PC-3 cells[1].
PROTAC CBP/p300/BRD4 Degrader-1 (combined with Paclitaxel (HY-B0015) at dose ratios of 1:2 and 1:3) exerts synergistic antiproliferative effects with Paclitaxel in PC-3 cells, with IC50 values of 5.59 nM (1:2) and 7.83 nM (1:3), respectively[1].
PROTAC CBP/p300/BRD4 Degrader-1 (0.1 nM-1000 nM; 12 h, 24 h) degrades BRD4, CBP and p300 in a concentration-dependent manner in PC-3 cells, DU145 cells and RM-1 cells, with a DC50 value of 8.8 pM for BRD4, 6.55 nM for CBP and 1.05 nM for p300 in PC-3 cells; it degrades in a time-dependent manner[1].
PROTAC CBP/p300/BRD4 Degrader-1 (1 nM, 24 h) downregulates the expression of c-Myc and Ac-H3K27, and degrades BRD2 and BRD3 with a hook effect in PC-3 cells[1].
PROTAC CBP/p300/BRD4 Degrader-1 (30 nM; 12 h for BRD4, 24 h for CBP/p300) degrade BRD4 and CBP/p300 is reversible in PC-3 cells, with protein levels recovering within 48 h after compound wash-out[1].
PROTAC CBP/p300/BRD4 Degrader-1 (1.0 nM for BRD4, 30 nM for CBP/p300; 12 h for BRD4, 24 h for CBP/p300) degrades BRD4 and CBP/p300 in a CRBN- and proteasome-dependent manner in PC-3 cells[1].
PROTAC CBP/p300/BRD4 Degrader-1 (1.0 nM for BRD4, 30 nM for CBP/p300; 6 h for BRD4, 12 h for CBP/p300) requires the formation of a ternary complex to degrade BRD4 and CBP/p300 in PC-3 cells, and the degradation is attenuated by pretreatment with Thalidomide (HY-14658) (10.0 μM) or cotreatment with NEO2734 (HY-136938) (10.0 μM)[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:PC-3 cells
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Concentration:-0.5, 0.0, 0.5, 1.0, 1.5, 2.0, 2.5 Log10(nM)
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Incubation Time:48 h
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Result:Exhibits significantly superior antiproliferative activity, with an IC50 value of 8.56 nM. When it is combined with PTX at molar ratios of 1:2 and 1:3, the IC50 values of the combination treatments decrease further to 5.59 nM and 7.83 nM, respectively, indicating that combination treatment enhances the antiproliferative effect on PC-3 cells.
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Cell Line:PC-3, DU145, RM-1
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Concentration:0.1 nM, 0.3 nM, 1 nM, 3 nM, 10 nM, 30 nM, 100 nM, 300 nM, 1000 nM (for BRD4/CBP/p300 degradation), 1.0 nM (for BRD4), 30 nM (for CBP/p300/wash-out assay)
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Incubation Time:24 h (for BRD4), 12 h-48 h (for CBP/p300), 6 h-12 h (for ternary complex assay)
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Result:Degrades BRD4, CBP and p300 in concentration- and time-dependent manner; downregulates c-Myc and Ac-H3K27 expression; degrades BRD2 and BRD3 with hook effect (no hook effect for BRD4); efficiently degrades BRD4, CBP and p300 in DU145 and RM-1 cells; degradation of BRD4 and CBP/p300 is reversible (protein levels recover within 48 h after wash-out in PC-3 cells); degradation is CRBN- and proteasome-dependent (blocked by siRNA CRBN, MG132, MLN4924); requires ternary complex formation.
| Species | Dose | Route | T1/2 | Tmax | AUC0-t | AUC0-∞ | Cmax | F | CL | Vz |
|---|---|---|---|---|---|---|---|---|---|---|
| Rat[1] | 1.0 mg/kg | i.v. | 3.26 h | / | 436 ng·h/mL | 438 ng·h/mL | 960 ng/mL | / | 39.8 mL/min/kg | 11.8 L/kg |
| Rat[1] | 1.0 mg/kg | i.p. | 2.31 h | 0.83 h | 224 ng·h/mL | 233 ng·h/mL | 59.4 ng/mL | 54.7 % | / | / |
| Rat[1] | 10.0 mg/kg | p.o. | 1.47 h | 0.33 h | 27.4 ng·h/mL | 27.9 ng·h/mL | 24.4 ng/mL | 0.64 % | / | / |
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:NOD-SCID (male, 6 weeks old, PC-3 human prostate cancer cells xenograft model)[1]
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Dosage:0.1 mg/kg; 0.2 mg/kg
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Administration:i.p.; every other day; 24 days
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Result:Achieved a tumor growth inhibition (TGI) of 55.6% at 0.1 mg/kg.
Achieved a TGI of 81.5% at 0.2 mg/kg, which was significantly more potent than positive controls NEO2734 (67.9% TGI at 20 mg/kg) and paclitaxel (64.1% TGI at 5 mg/kg).
Confirmed dose-dependent degradation of CBP, p300, and BRD4 via IHC staining of tumor tissues.
Showed a substantial increase in apoptotic cells in treated groups via TUNEL staining, greater than that observed with NEO2734 or Paclitaxel.
Revealed no observable histopathological abnormalities in major organs (liver, heart, spleen, lung, kidney) via H&E staining, and routine blood assays showed no significant changes in markers of organ function.
Chemical Information
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CAS No. 3109024-12-3
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Masse moléculaire 801.81
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Formule C41H42F3N7O7
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SMILES
O=C1N(C(C2=C1C=CC(N3CCC(CC3)C(N4CCC(CC4)C5=NC6=CC=C(C=C6N5CCOC(F)(F)F)C(C=C7C)=CN(C7=O)C)=O)=C2)=O)C(C(N8)=O)CCC8=O
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureté et documentation
Références
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
PROTAC CBP/p300/BRD4 Degrader-1 Related Classifications
HY-181758 Related Classifications
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