SEL120-34A is a novel CDK8 inhibitor active in AML cells with high levels of serine phosphorylation of STAT1 and STAT5 transactivation domains

by Selleckchem | Aug 31 2023

Inhibition of oncogenic transcriptional programs is a promising therapeutic strategy. A substituted tricyclic benzimidazole, SEL120-34A, is a novel inhibitor of Cyclin-dependent kinase 8 (CDK8), which regulates transcription by associating with the Mediator complex. X-ray crystallography has shown SEL120-34A to be a type I inhibitor forming halogen bonds with the protein's hinge region and hydrophobic complementarities within its front pocket. SEL120-34A inhibits phosphorylation of STAT1 S727 and STAT5 S726 in cancer cells in vitro. Consistently, regulation of STATs- and NUP98-HOXA9- dependent transcription has been observed as a dominant mechanism of action in vivo. Treatment with the compound resulted in a differential efficacy on AML cells with elevated STAT5 S726 levels and stem cell characteristics. In contrast, resistant cells were negative for activated STAT5 and revealed lineage commitment. In vivo efficacy in xenotransplanted AML models correlated with significant repression of STAT5 S726. Favorable pharmacokinetics, confirmed safety and in vivo efficacy provide a rationale for the further clinical development of SEL120-34A as a personalized therapeutic approach in AML.

Comments:

The information you provided describes the potential therapeutic strategy of inhibiting oncogenic transcriptional programs, with a specific focus on a novel inhibitor called SEL120-34A. This compound targets Cyclin-dependent kinase 8 (CDK8), a protein involved in regulating transcription through its interaction with the Mediator complex.

SEL120-34A has been characterized as a type I inhibitor, meaning it binds to the active site of CDK8. X-ray crystallography studies have revealed that the compound forms halogen bonds with the hinge region of the protein and exhibits hydrophobic complementarity within the front pocket of CDK8.

In vitro experiments have demonstrated that SEL120-34A inhibits the phosphorylation of STAT1 at S727 and STAT5 at S726 in cancer cells. This inhibition suggests that the compound disrupts the activity of these signaling proteins, which play important roles in oncogenic transcriptional programs. Additionally, in vivo studies have observed that SEL120-34A affects the regulation of transcription dependent on STATs and NUP98-HOXA9, further supporting its mechanism of action.

Interestingly, SEL120-34A exhibited varying efficacy on acute myeloid leukemia (AML) cells depending on their levels of activated STAT5 at S726 and their stem cell characteristics. Cells with elevated STAT5 S726 levels and stem cell properties showed greater sensitivity to the compound, while resistant cells lacking activated STAT5 demonstrated lineage commitment.

Furthermore, the in vivo efficacy of SEL120-34A in xenotransplanted AML models correlated with a significant reduction in STAT5 S726 levels. This suggests that the compound's effectiveness in these models is associated with its ability to suppress the activity of STAT5.

Importantly, SEL120-34A has demonstrated favorable pharmacokinetics, safety, and in vivo efficacy, providing a strong rationale for its further development as a personalized therapeutic approach for AML. These findings suggest that SEL120-34A could be a promising candidate for clinical trials and potentially offer new treatment options for patients with AML.