BRD4/CK2-IN-1

BRD4/CK2-IN-1 is the first highly effective and oral active dual-target inhibitor of BRD4/CK2 (bromodomain-containing protein 4/casein kinase 2), with IC 50 s of 180 nM and 230 nM for BRD4 and CK2 , respectively. BRD4/CK2-IN-1 has strong anticancer activity without obvious toxicities. BRD4/CK2-IN-1 induces apoptosis and autophagy -associated cell death in triple-negative breast cancer (TNBC) In Vitro BRD4/CK2-IN-1 (compound 44e) (0-25 μM; 24 hours) has anti-proliferation effect with IC 50 s of 2.66 and 3.52 μM in MDA-MB-231 and MDA-MB-468 cells, respectively. BRD4/CK2-IN-1 (0-10 μM; 24 hours) dose-dependently induces apoptosis of MDA-MB-231 and MDA-MB-468 cells. BRD4/CK2-IN-1 (0-10 μM; 24 hours) dose-dependently downregulates Bcl-2 but upregulates Bax and cleaved caspase-3. BRD4/CK2-IN-1 (0-10 μM; 24 hours) significantly downregulates the autophagy substrate p62 and up-regulated beclin-1 and LC3II in MDA-MB-231 and MDA-MB. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Cell Viability AssayCell Line: MDA-MB-231, MDA-MB-468 cells Concentration: 0, 0.19, 0.39, 0.78, 1.56, 3.13, 6.25, 12.5, 25 μM Incubation Time: 24 hours Result: Showed anti-proliferative rates in MDA-MB-231 and MDA-MB-468 cells (IC 50 = 2.66 and 3.52 μM, respectively). Apoptosis AnalysisCell Line: MDA-MB-231, MDA-MB-468 cells Concentration: 0, 2.5, 5, 10 μM Incubation Time: 24 hours Result: Dose-dependently induced apoptosis of MDA-MB-231 and MDA-MB-468 cells. Western Blot AnalysisCell Line: MDA-MB-231, MDA-MB-468 cells Concentration: 0, 2.5, 5, 10 μM Incubation Time: 24 hours Result: Dose-dependently downregulated Bcl-2 but upregulated Bax and cleaved caspase-3. Cell Line: Concentration: Incubation Time: Result: In Vivo BRD4/CK2-IN-1 (25 and 50 mg/kg; intragastric administration; daily for 19 days) inhibits tumor growth in TNBC xenograft models . BRD4/CK2-IN-1 (25 and 50mg/kg; intragastric administration; daily for 19 days) shows weak toxicity measured by body weight loss in the MDA-MB-231 and MDA-MB-468 xenograft models . Preliminary Assessment of Pharmacokinetics (PK) profile of BRD4/CK2-IN-1 . Parameter iv (1 mg/kg) po (10 mg/kg) T 1/2 (h) 4.21±0.57 5.14±0.71 C max (ng/mL) 237±11 206±6 AUC 0- t (ng·h/mL) 579±49 2079±130 AUC 0-∞ (ng·h/mL) 588±36 2090±146 V Z (L/kg) 21.1±2.6 CL ((mL/min)/kg) 57.4±1.3 F (%) 32.5 MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: Female nude mice (BALB/c, 6-8 weeks, 20-22 g) bearing MDA-MB-231 cells Dosage: 25 and 50 mg/kg Administration: Intragastric administration; daily for 19 days Result: Had the most pronounced tumor growth inhibition (TGI) (63.8%) in the MDA-MB-231 xenograft tumor model at 50 mg/kg. Form:Solid IC50& Target:BRD4 180 nM (IC 50 ) CK2 230 nM (IC 50 )

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