CDK8-IN-11 is a potent and selective inhibitor of CDK8 with an IC50 of 46 nM, effectively targeting the WNT/β-catenin signaling pathway and showing potential applications in colon cancer research [1].

CDK8-IN-11, identified as compound 29 at a concentration of 200 nM, demonstrates a 73.6% inhibition of CDK8, along with a substantial inhibitory effect on cell proliferation across various cell lines (HCT-116, HHT-29, SW480, CT-26, GES-1) at concentrations ranging from 0-50 μM over 48 hours. Furthermore, at concentrations of 0-4 μM for the same duration, it hinders the CDK8-mediated phosphorylation of STAT1 at Ser727 in HCT-116 cells. This compound also disrupts canonical WNT/β-catenin signaling pathways and interferes with β-catenin-mediated transcription in HCT-116 cells at 0-4 μM over 24 hours, while promoting an increase in the G1 phase cell population within a concentration range of 0.5-2 μM over 48 hours. Moreover, it effectively reverses Sorafenib resistance in HCT-116 cells at concentrations between 0-4 μM. Through cell proliferation assays and Western blot analysis, CDK8-IN-11 is shown to inhibit cell growth and STAT1 phosphorylation at precise concentrations without affecting JAK-regulated phosphorylation at Tyr701, alongside adjustments in the cell cycle, culminating in decreased G2/M and S phases in HCT-116 cells.

CDK8-IN-11, at dosages of 10 and 40 mg/kg administered orally (p.o.), effectively inhibits tumor growth in CT-26 xenograft mice, significantly reducing both tumor volume and levels of β-catenin and c-Myc in the tumor. Additionally, a high dose of 1000 mg/kg given orally to ICR mice showed no signs of abnormal behavior within a seven-day observation period. Furthermore, CDK8-IN-11 demonstrated moderate permeability in rats with dosages of 10 mg/kg (p.o.) and 2 mg/kg (intravenously, i.v.), evidenced by an apparent permeability coefficient of 1.8 × 10^6 cm/s. The pharmacokinetic profile of CDK8-IN-11 in rats included a half-life (T 1/2) of 1.1 hours, a time to reach maximum concentration (T max) of 0.8 hours, and a maximum concentration (C max) of 453 ng/mL after oral administration (10 mg/kg), with a bioavailability (F) of 31.7%. Conversely, the intravenous administration (2 mg/kg) resulted in a T 1/2 of 0.5 hours and a C max of 318 ng/mL.