PLK1/BRD4-IN-1

PLK1/BRD4-IN-1 (9b) is an orally active dual PLK1 and BRD4 inhibitor with IC50 values of 22 nM and 109 nM against PLK1 and BRD4, respectively. PLK1/BRD4-IN-1 induces cell cycle arrest and apoptosis, downregulates the transcription of several proliferation-related oncogenes, and exhibits favorable in vivo antitumor activity[1].

Signaling Pathways >> Apoptosis >> Apoptosis

Research Areas >> Cancer

Signaling Pathways >> Cell Cycle/DNA Damage >> Polo-like Kinase (PLK)

Signaling Pathways >> Epigenetics >> Epigenetic Reader Domain

BRD4:109 nM (IC50)

PLK1:22 nM (IC50)

PLK1/BRD4-IN-1 (9b) (72 h) shows broad-spectrum antiproliferative activities[1]. PLK1/BRD4-IN-1 (0-9 µM, 24 h) induces cell cycle arrest[1]. PLK1/BRD4-IN-1 (0-9 µM, 48 h) induces cell apoptosis[1]. PLK1/BRD4-IN-1 inhibits the proliferative of cancer cells by exerting its inhibitory activity on both PLK1 and BRD4[1]. Cell Viability Assay[1] Cell Line: MV4-11, LnCap, HT-29, A375, SKOV-3 Concentration: Cells were maintained in RPMI 1640 or DMEM medium supplemented with 10% FBS (v/v) in 5% CO2, except for MV4-11 cells, which were cultured in IMDM medium. Incubation Time: 72 h Result: Showed broad-spectrum antiproliferative activities with IC50 values of 0.13, 0.14, 1.10, 2.82 and 2.51 µM against MV4-11, LnCap, SKOV-3, A375 and HT29 cells, respectively. Cell Cycle Analysis[1] Cell Line: MV4-11 Concentration: 0.1, 0.3, 1, 3, 9 µM Incubation Time: 24 h Result: Induced obvious G2/M arrest in a concentration-dependent manner Apoptosis Analysis[1] Cell Line: MV4-11 Concentration: 0.1, 0.3, 1, 3, 9 µM Incubation Time: 48 h Result: Significantly increased the number of Annexin V/PI-positive MV4-11 cells in a concentration-dependent manner. RT-PCR[1] Cell Line: MV4-11 Concentration: 0.1, 0.3, 1, 3, 9 µM Incubation Time: 24 h Result: Reduced the transcription of c-MYC and MYCN as well as BCL-2, in a concentration-dependent manner. Western Blot Analysis[1] Cell Line: MV4-11 Concentration: 0.1, 0.3, 1, 3, 9 µM Incubation Time: 48 h Result: Decreased the expression of c-Myc and Bcl-2 in a concentration dependent-manner and upregulated cleaved caspase-3 and cleaved PARP.

PLK1/BRD4-IN-1 (9b) (60 mg/kg/d; IG; 18 days) results in a significant decrease in average tumor size, with no obvious toxicity[1]. Animal Model: Five weeks old male NOD-SCID mice[1]. Dosage: 60 mg/kg/d Administration: Oral gavage, 18 days; tumor xenograft models were established by subcutaneously injecting 100 µL of 1×108 cell/mL MV4-11 cell suspension into NOD-SCID mice. Result: Resulted in a significant decrease in average tumor size, with 66% tumor growth inhibition, and didn’t obviously affect the body weight of mice.

[1]. Ning-Yu Wang, et al. Design, synthesis, and biological evaluation of 4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridine derivatives as novel dual-PLK1/BRD4 inhibitors. Eur J Med Chem. 2020 Apr 1;191:112152.