A1874

A1874 is an orally active BRD4 PROTAC degrader with a DC₅₀ of 32 nM. A1874 degrades BRD4 via the ubiquitin-proteasome system by recruiting the MDM2 E3 ligase, while disrupting the MDM2-p53 interaction to stabilize p53 and upregulate p21, thereby inducing cell cycle arrest and apoptosis. A1874 exhibits selectivity for wild-type p53 cells and MDM2-amplified tumors, and it can be used in research on breast cancer, colorectal cancer, melanoma, lung cancer, lymphoma, myeloid leukemia, osteosarcoma, and glioblastoma^{[1][2][3][4][5]}. IC50 & Target:DC50: 32 nM (induce BRD4 degradation in cells)^[1]. In Vitro:A1874 exhibits nanomolar cytotoxic activity, induces BRD4 degradation, G1-phase arrest, and inhibits colony formation, proliferation and migration in p53 wild-type breast cancer cell lines, including Tamoxifen (HY-13757A)-resistant ER+ cells; whereas p53 mutant breast cancer cell lines only show micromolar sensitivity^[5].
A1874 (5-500 nM; 24 h-10 d) potently inhibits the viability, proliferation, cell cycle progression, migration and invasion abilities of primary human colon cancer cells (pCan1, pCan2, pCan3, pCan4) and established HCT116 colon cancer cells^[2].
A1874 (25 nM-10 μM; 24 h) potently degrades BRD4 (DC₅₀ = 32 nM, D_max = 98%), reduces c-Myc expression by 85%, stabilizes p53 up to 5.9-fold, and induces p21^CIP1/WAF1 expression in wild-type p53 HCT116 colon cancer cells after 24 h of incubation^[1].
A1874 (10 nM-10 μM; 48 h) reduces the viability of wild-type p53 HCT116 colon cancer cells by 97% after 48 h of incubation, and exhibits synergistic activity at concentrations of 100 nM and above^[1].
A1874 (10 nM-10 μM; 48 h) reduces the survival rate of wild-type p53 A375 melanoma cells by 98% after 48 h of incubation, and exhibits synergistic activity at concentrations of 250 nM and higher^[1].
A1874 (10 nM-10 μM; 48 h) exhibits only extremely low antiproliferative activity in p53-mutant NCI-H2030 lung cancer cells (with a 22.4% decrease in cell viability at 10 μM) and HT29 colon cancer cells (with no decrease in viability), and its activity is reduced in p53-deficient HCT116 colon cancer cells after 48 h of incubation^[1].
Incubation with A1874 (10 nM-10 μM; 48 h) reduces the viability of Daudi lymphoma cells by 70%, MOLM-13 myeloid leukemia cells by 95%, and wild-type p53 SJSA1 osteosarcoma cells overexpressing MDM2 by 97.5% (IC₅₀ = 46.5 nM)^[1].
A1874 (8-2000 nM; 18 h) induces concentration-dependent degradation of BRD4, and upregulates the protein levels of MDM2, p21 and p53 in MCF7 (p53 wild-type), HT1080 (p53 wild-type), LNCAP (p53 wild-type) and HFF (p53 wild-type) cells after 18 h of treatment^[3].
A1874 (8-2000 nM; 18 h at 32°C or 37°C) induces concentration-dependent degradation of BRD4 and upregulates the protein levels of MDM2 and p53 in HT1376 (p53^P250L) and H441 (p53^R158L) cells after 18 h of treatment at 32°C, while no such effects are observed after treatment at 37°C^[3].
A1874 (500 nM; 18 h) induces BRD4 degradation and upregulates the protein levels of MDM2 and p53 in HCT116 cells after 18 h of treatment; when combined with Doxorubicin (HY-15142A), Camptothecin (HY-16560) or Mitomycin C (HY-13316), it dose-dependently inhibits A1874-induced BRD4 degradation by downregulating MDM2 expression, whereas combination with Etoposide (HY-13629) does not interfere with the activity of A1874^[3].
A1874 (666 nM; 18 h) induces BRD4 degradation in A549, U2OS, SJSA, JAR and A875 cells after treatment at 666 nM for 18 h, with higher activity in cell lines with higher MDM2 expression levels; however, despite the high MDM2 expression level in CCF-STTG1 cells, A1874 fails to induce BRD4 degradation in JEG3 or CCF-STTG1 cells^[3].
A1874 (8-2000 nM; 18 h) induces BRD4 degradation and MDM2 expression in p53-functional JAR and CCF-STTG1 cells, but exerts no such effects in p53-inactivated JAR-E6 and CCF-STTG1-E6 cells^[3].
A1874 (72 h) potently reduces the viability of U-87 MG cells (IC₅₀ = 0.146 μM) and Temozolomide (HY-17364)-resistant U-87 MG TR cells (IC₅₀ = 0.319 μM)^[4].
After delivery via a targeted formulation, the intracellular level of A1874 (25 μM; 2 h) in bEnd.3 cells reaches 0.61 pg/cell, with an uptake over 5-fold higher than that delivered via a non-targeted formulation; free PC can partially inhibit this uptake process, indicating that its transport is mediated by OCTN2^[4].
A1874 induces significant degradation of nuclear BRD4 protein in U-87 MG cells and temozolomide-resistant U-87 MG TR cells, while it increases the expression levels of c-Myc and MDM2 proteins and elevates the content of nuclear TP53 in U-87 MG cells^[4].
A1874 upregulates BRD4 mRNA expression and downregulates p53 mRNA expression in U-87 MG cells, but exerts no significant effect on the mRNA expression of BRD4, c-Myc or p53 in Temozolomide-resistant U-87 MG TR cells^[4].
When tested in combination with PRONano, A1874 (200 nM; 24 h) alters the protein expression levels of BRD4, TP53, MDM2 and C-Myc in U-87 MG and U-87 MG TR glioblastoma cells^[5].
When tested together with PRONano, A1874 (100 μM) alters the gene expression levels of BRD4, MYC and TRP53 in cultured glioblastoma cells^[5].
When tested in combination with PRONano, A1874 (0.1 μM; administered once every two days for a total of 8 days) alters the growth of U-87 MG glioblastoma 3D multicellular tumor spheres, which can be detected by changes in diameter and surface area^[5].
A1874 (8-2000 nM; 18 h) requires functional wild-type p53 to induce MDM2 expression and achieve efficient BRD4 degradation in JAR and CCF-STTG1 cells^[3].
A1874 (8-2000 nM; 18 h) does not induce BRD4 degradation or alter MDM2 protein levels in UC3 (p53^F113C) or UC3-p53KO cells following 18 h of treatment^[3].
A1874 (25-500 nM; 24 h-72 h) induces caspase-dependent mitochondrial apoptosis in primary human colon cancer cells (pCan1, pCan2, pCan3, pCan4) and established HCT116 colon cancer cells^[2].
A1874 (100 nM; 8 h-72 h) induces BRD4 degradation and downregulates BRD4-dependent genes (c-Myc, Bcl-2, cyclin D1) in primary human colon cancer cells (pCan1, pCan2)^[2].
A1874 (100 nM; 8 h-72 h) induces p53 protein stabilization and oxidative damage (ROS production, decreased GSH/GSSG ratio, DNA strand breaks) in primary human colon cancer cells (pCan1, pCan2) via a BRD4-independent mechanism^[2]. In Vivo:A1874 (20 mg/kg; p.o.; once daily for 21 days) potently inhibits colon cancer xenograft growth in SCID mice, associated with BRD4 degradation, apoptosis activation, p53 elevation, and oxidative stress in tumor tissues analyzed at Day 7^[2].