2. PROTAC Epigenetics Apoptosis
  3. PROTACs Epigenetic Reader Domain Histone Acetyltransferase c-Myc Apoptosis
  4. 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.

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PROTAC CBP/p300/BRD4 Degrader-1

PROTAC CBP/p300/BRD4 Degrader-1 Chemical Structure

CAS No. : 3109024-12-3

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PROTAC CBP/p300/BRD4 Degrader-1 Related Antibodies

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Description

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[1].

IC50 & Target[1]

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)

In Vitro

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.

PROTAC CBP/p300/BRD4 Degrader-1 Related Antibodies

Cell Proliferation Assay[1]

Cell Line: PC-3 cells
Concentration: -0.5, 0.0, 0.5, 1.0, 1.5, 2.0, 2.5 Log10(nM)
Incubation Time: 48 h
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.

Western Blot Analysis[1]

Cell Line: PC-3, DU145, RM-1
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)
Incubation Time: 24 h (for BRD4), 12 h-48 h (for CBP/p300), 6 h-12 h (for ternary complex assay)
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.
Parmacokinetics
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 % / /
In Vivo

PROTAC CBP/p300/BRD4 Degrader-1 (29c) (0.1-0.2 mg/kg; i.p.; every other day; 24 days) exhibits potent dose-dependent antitumor activity in a PC-3 prostate cancer xenograft model, achieving 81.5% tumor growth inhibition at a dose of 0.2 mg/kg, with a favorable safety profile[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Model: NOD-SCID (male, 6 weeks old, PC-3 human prostate cancer cells xenograft model)[1]
Dosage: 0.1 mg/kg; 0.2 mg/kg
Administration: i.p.; every other day; 24 days
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.
Molecular Weight

801.81

Formula

C41H42F3N7O7
CAS No.
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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PROTAC CBP/p300/BRD4 Degrader-1 Related Classifications

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Keywords:

PROTAC CBP/p300/BRD4 Degrader-13109024-12-3PROTACsEpigenetic Reader DomainHistone Acetyltransferasec-MycApoptosisHATsHATMycacetyl-H3K27CRBNxenograft modelsCBP/p300colorectal cancerPC-3 prostate cancer cellsBRD4proteasomeprostate cancerInhibitorinhibitorinhibit

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