CDK8 Inhibitor

CDK8-IN-20 (Compound 67j) is a selective, potent and orally active type I CDK8 inhibitor with an IC₅₀ of 70.5 nM. CDK8-IN-20 shows IC₅₀ values of 147.8, 726.9 and 217.4 nM for homologous kinase CDK19, CDK7 and CDK9. CDK8-IN-20 can inhibit the Wnt/β-catenin pathway and downregulate the expression of β-catenin, Cyclin D1, and c-Myc. CDK8-IN-20 can induce ROS production and cause G2/M and S phase arrest. CDK8-IN-20can be used for the research of cancer, such as colon cancer.

KB-0742 hydrochloride is a potent, selective and orally active CDK9 inhibitor with an IC₅₀ of 6 nM for CDK9/cyclin T1. KB-0742 hydrochloride is selective for CDK9/cyclin T1 with >50-fold selectivity over other CDK kinases. KB-0742 hydrochloride has potent anti-tumor activity.

CDK8-IN-19 (Compound 3d) is a CDK8 inhibitor with an IC₅₀ of 25.08 nM. CDK8-IN-19 has a broad-spectrum anticancer activity, such as leukemia, melanoma and breast cancer, without significant cytotoxic effect on the normal Vero cells (mean IC₅₀s of 2.87, 3.65, 3.79 and 45.48 μM, respectively).

CDK8-IN-18 (compound BRD-2299) is a potent inhibitor of CDK8, with the IC₅₀ of 43 μM. CDK8-IN-18 plays an important role in cancer research.

SW393109 is a CDK8 inhibitor with an IC₅₀ of 3.16 nM and an EC₅₀ of 5 nM against the DKK1 reporter gene. SW393109 inhibits IFNγ-induced phosphorylation of STAT1 S727, impairs the EWSR1::FLI1 transcriptional program in Ewing sarcoma cells and suppresses tumor cell proliferation. SW393109 acts as a gain-of-function molecular trap that induces the retention of the CDK8 kinase module (CKM) and Mediator complex on chromatin. SW393109 can be used in studies related to Ewing sarcoma.

SNX631 is an orally active and selective CDK8/CDK19 inhibitor. SNX631 reduces the phosphorylation of STAT1/STAT3 S727, and upregulates miR-21-5p, miR-21-3p and miR-221 in cancer cells. SNX631 transcription-independently inhibits meiotic resumption in mouse oocytes, blocks nuclear envelope breakdown, first polar body extrusion and mitochondrial expansion and aggregation, with no cytotoxicity. SNX631, in combination with Lapatinib (HY-50898) or Trastuzumab (HY-P9907), synergistically inhibits cancer cell growth, upregulates the tumor suppressor BTG2, prevents Lapatinib-induced upregulation of oncogenic miRNAs, overcomes drug resistance, reduces the infiltration of αSMA+ stromal fibroblasts and ARG1+ M2 macrophages, and exhibits favorable biosafety. SNX631 can be used in studies related to HER2-positive breast cancer and cancer.

CDK8-IN-15 (Compound 46) is a potent CDK8 inhibitors with an IC₅₀ value of 57 nM. It can enhance the thermal stability of CDK8 along with inhibition against NF-κB and have favourable selectivity across the CDK family and tyrosine kinase. Additionally, it also demostrates a positive effect in vitro psoriasis model induced by TNF-α and alleviats the inflammatory response enhancing the expression of Foxp3 and IL-10, which is promising for research of psoriasis diseases.

LS-Q2 is a highly selective CDK4/9 inhibitor with IC₅₀ values of 1.4 nM and 6.2 nM. LS-Q2 inhibits cancer cells proliferation, induces G2/M phase arrest, apoptosis and reduces pSer2 RNA polymerase II expression. LS-Q2 interacts synergistically with BET and Bcl-2 inhibitors to drive antitumor activity. LS-Q2 can be used for the research of cancer, such as malignant solid tumors.

CDK8/BRD4-IN-1 is a dual CDK8/BRD4 inhibitor, with an IC₅₀ of 5.44 μM against CDK8 and an IC₅₀ of 4.03 μM against BRD4. CDK8/BRD4-IN-1 exhibits anticancer activity against colorectal cancer. CDK8/BRD4-IN-1 can be used for the research of colorectal cancer.

CDK8/19-IN-2 (compound 12) is an orally active and potent cyclin-dependent kinase 8/19 (CDK8 and CDK19) inhibitor, with IC₅₀ values of 2.08 and 2.49 nM, respectively. CDK8/19-IN-2 can be used for acute myeloid leukemia (AML), breast cancer, and lymphoma research.

MK256 is an orally active, selective CDK8 inhibitor and CDK19/cyclin C inhibitor with IC₅₀ values of 2.5 nM and 3.3 nM, respectively. MK256 downregulates phosphorylated STAT1 ^(S727), STAT5 ^(S726), MCL-1 mRNA and CCL2 mRNA. MK256 exhibits anti-tumor activity in acute myeloid leukemia. MK256 can be used for the research of acute myeloid leukemia.

CDK8-IN-16 (Compound 51) is an orally active dual inhibitor for CDK8 and CDK19 wih IC₅₀ of 5.1 nM and 5.6 nM. CDK8-IN-16 inhibits the phospho-STAT1^SER727 with an IC₅₀ of 17.9 nM in SW620 cell, inhibits WNT signaling pathway with an IC₅₀ of 7.2 nM in 7dF3 cell. CDK8-IN-16 exhibits good pharmacokinetic characteristics in rat models with an oral bioavailability of 57%.