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F146-1740

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Background Information of F146-1740

F146-1740 is a novel cyclin-dependent kinase 8 (CDK8) inhibitor. The inhibition rate is 16.0±2.3% at 10 μM. CDK8 gene expression correlates with increased mortality in colorectal, breast, and ovarian cancers and its overexpression is essential for the proliferation of cancer cells. Due to its key roles in oncogenesis, CDK8 has recently attracted considerable attention. Inhibitors of CDK8 offer a novel strategy for the treatment of various cancers.

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Mechanism and Indications

Signaling Pathways Cell Cycle/DNA Damage
Target CDK
Research Area Neurological Disease
Indications

Clinical Information

Product Name Sponsor & Collaborators Indications Start Date End Date Phase

Chemical Information

M.Wt Formula CAS No. Synonyms
367.44 C24H21N3O

Structure Information of F146-1740

Smiles C1C=CC(C2C(C(N(C3C=C(C)C(C)=CC=3)C)=O)=C3C=CC=CC3=NN=2)=CC=1
InChI InChI=1S/C24H21N3O/c1-16-13-14-19(15-17(16)2)27(3)24(28)22-20-11-7-8-12-21(20)25-26-23(22)18-9-5-4-6-10-18/h4-15H,1-3H3

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Chemical and Physical Properties

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Reference

[1].He LJ, et al. Shape-based virtual screen for the discovery of novel CDK8 inhibitor chemotypes. Bioorg Med Chem Lett. 2019 Feb 15;29(4):549-555.
With the aim of discovering novel cyclin-dependent kinase 8 (CDK8) inhibitors, a combined similarity search and molecular docking approach was employed, which led to 32 hits. Biological tests led to the discovery of several novel submicromolar inhibitors. In particular, compound C768-0769 (ZC0201) showed good CDK8 inhibitory activity, and compound ZC0201 effectively suppressed HCT-116 colorectal cancer cell proliferation by inducing G1/S transition arrest. Furthermore, modulation of phosphorylated signal transducer and activator of transcription 1 (Ser 727) (STAT1SER727), a pharmacodynamic biomarker of CDK8 activity, demonstrated that ZC0201 may cause G1/S transition arrest through CDK8 activity inhibition. Due to its good cellular activity, ZC0201 may be an ideal lead compound for further modification as a potential cancer therapeutic agent.

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