PROTAC CBP/p300/BRD4 Degrader-1

PROTAC CBP/p300/BRD4 Degrader-1 is a dual-targeting PROTAC degrader with DC50 values of 8.8 pM for BRD4, 6.55 nM for CBP, and 1.05 nM for p300. It facilitates CRBN and proteasome-dependent degradation of BRD4 and CBP/p300, leading to the downregulation of c-Myc and acetyl-H3K27, and triggers apoptosis. As an antiproliferative and antitumor agent, PROTAC CBP/p300/BRD4 Degrader-1 demonstrates tumor growth inhibition in xenograft models. It is applicable in research on prostate and colorectal cancers.

BRD4:8.8 pM (DC50)

PROTAC CBP/p300/BRD4 Degrader-1 (29c) exhibits significant antiproliferative effects on 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), while demonstrating low cytotoxicity against normal human prostate epithelial cells RWPE-1 (IC₅₀ = 4.38 μM). The selectivity index (SI) is greater than 1500 for PC-3/RWPE-1 and greater than 600 for DU145/RWPE-1, with nanomolar antiproliferative activity observed across various colorectal cancer cell lines. In biochemical assays, PROTAC CBP/p300/BRD4 Degrader-1 shows inhibitory activity against BRD4 (BD1) with an IC₅₀ of 44.6 nM, BRD4 (BD2) with 13.1 nM, p300 with 102.6 nM, and CBP with 110.8 nM. It binds strongly to CRBN, with a Kd of 3.24 μM. The compound exhibits time-dependent antiproliferative effects against PC-3 cells at 24, 48, 72, and 96 hours. When combined with Paclitaxel at a 1:2 and 1:3 ratio, it synergistically enhances antiproliferative activity in PC-3 cells, with IC₅₀ values of 5.59 nM and 7.83 nM, respectively. It facilitates degradation of BRD4, CBP, and p300 in PC-3, DU145, and RM-1 cells in a concentration-dependent manner within 12 to 24 hours; with DC₅₀ values in PC-3 cells of 8.8 pM for BRD4, 6.55 nM for CBP, and 1.05 nM for p300, the degradation is time-dependent. At 24 hours and 1 nM, the compound downregulates c-Myc and Ac-H3K27 in PC-3 cells and degrades BRD2 and BRD3 through a hook effect. At 30 nM, it degrades BRD4 and CBP/p300 in PC-3 cells within 12 to 24 hours, with reversibility seen by the restoration of protein levels within 48 hours after compound removal. Degradation of BRD4 and CBP/p300 in PC-3 cells depends on CRBN and the proteasome at concentrations of 1.0 nM for BRD4 and 30 nM for CBP/p300. The formation of a ternary complex is necessary for degradation; pretreatment with Thalidomide (10.0 μM) or co-treatment with NEO2734 (10.0 μM) can reduce this effect.

PROTAC CBP/p300/BRD4 Degrader-1 (29c), administered at 0.1-0.2 mg/kg via intraperitoneal injection every other day over a period of 24 days, demonstrates potent dose-dependent antitumor activity in vivo within the PC-3 prostate cancer xenograft model. At a dose of 0.2 mg/kg, it achieves an 81.5% tumor growth inhibition rate, with a favorable safety profile.