BRD4/CK2-IN-1

• CAT Number: I045158
• CAS Number: 2756851-99-5
• Molecular Formula: C29H30ClN5O5
• Molecular Weight: 564.03
• Purity: ≥95%
• Synonyms: N-[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]-2-[4-(5,7-dimethoxy-4-oxo-3H-quinazolin-2-yl)phenoxy]acetamide
• InChI: InChI=1S/C29H30ClN5O5/c1-34-10-12-35(13-11-34)24-9-6-19(14-22(24)30)31-26(36)17-40-20-7-4-18(5-8-20)28-32-23-15-21(38-2)16-25(39-3)27(23)29(37)33-28/h4-9,14-16H,10-13,17H2,1-3H3,(H,31,36)(H,32,33,37)
• InChIKey: UZWCUBDJHDWTFV-UHFFFAOYSA-N
• SMILES: CN1CCN(CC1)C2=C(C=C(C=C2)NC(=O)COC3=CC=C(C=C3)C4=NC5=C(C(=CC(=C5)OC)OC)C(=O)N4)Cl

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 IC50s 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)[1]
BRD4/CK2-IN-1 (compound 44e) (0-25 μM; 24 hours) has anti-proliferation effect with IC50s of 2.66 and 3.52 μM in MDA-MB-231 and MDA-MB-468 cells, respectively[1].
BRD4/CK2-IN-1 (0-10 μM; 24 hours) dose-dependently induces apoptosis of MDA-MB-231 and MDA-MB-468 cells[1].
BRD4/CK2-IN-1 (0-10 μM; 24 hours) dose-dependently downregulates Bcl-2 but upregulates Bax and cleaved caspase-3[1].
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[1].
BRD4/CK2-IN-1 (25 and 50 mg/kg; intragastric administration; daily for 19 days) inhibits tumor growth in TNBC xenograft models[1].
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[1].
Preliminary Assessment of Pharmacokinetics (PK) profile of BRD4/CK2-IN-1[1].

Parameter
iv (1 mg/kg)
po (10 mg/kg)

T1/2 (h)
4.21±0.57
5.14±0.71

Cmax (ng/mL)
237±11
206±6

AUC0-t (ng·h/mL)
579±49
2079±130

AUC0-∞ (ng·h/mL)
588±36
2090±146

VZ (L/kg)
21.1±2.6

CL ((mL/min)/kg)
57.4±1.3

F (%)

32.5

Reference

[1]. Zhang J, et al. Discovery of Novel Dual-Target Inhibitor of Bromodomain-Containing Protein 4/Casein Kinase 2 Inducing Apoptosis and Autophagy-Associated Cell Death for Triple-Negative Breast Cancer Therapy. J Med Chem. 2021;64(24):18025-18053.
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