RVU120: Novel Mediator Complex Inhibitor in MDS/AML

Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemias (AML) exhibit hematopoietic differentiation blocks linked to aberrant stage-specific transcription. The mediator complex kinase module, comprising CDK8, CDK19, Cyclin C, MED12, and MED13, acts as a molecular switch regulating gene expression, exploited by cancers to maintain an undifferentiated state. Opeyemi Ajibade and his team aimed to assess the efficacy of the RVU120, a first-in-class specific CDK8/19 inhibitor in Phase Ib clinical trial, stimulates erythroid differentiation in transformed CD34⁺ cord blood (CB) and Diamond-Blackfan Anemia (DBA) CD34x⁺ cells. Evaluating CDK8/19 inhibition’s therapeutic potential, aberrant mediator complex expression and erythroid-stimulating activity were confirmed in CD34⁺ primary samples of AML and MDS.

Researchers performed an inclusive analysis of mediator complex component expression in a comprehensive database of MDS CD34⁺ marrow samples and age-matched controls. Significantly, MED12 overexpression was observed in MDS samples, particularly in the refractory anemia with excess blasts (RAEB) subset of MDS(P=0.018), correlating with a higher risk of transformation to AML. Examination of MED12 expression in sorted leukemic stem cells from primary AML samples revealed elevated levels in Long Term Hematopoietic Stem Cells, from AML samples with both normal karyotype and complex karyotypes compared to healthy controls.

In evaluating mediator kinase module inhibition in the MDS-derived cell line (MDS-L), researchers found that CDK8/19 inhibition with RVU120 induced increased erythroid differentiation. This observation aligned with findings in transformed CD34⁺ CB cells, showing correlated phenotypic changes, inhibition of CDK8-dependent phosphorylation marker S726 on STAT5, and a significant upregulation of genes associated with erythroid commitment and hemoglobin metabolism. To confirm the therapeutic potential of CDK8/CDK19 inhibition in MDS and AML, a colony-forming assay was performed on  (n= 15) primary samples, demonstrating increased erythroid differentiation and changes in the expression of erythroid differentiation markers. Detailed analysis of the treated samples revealed augmented colony numbers, accompanied by increased CD71 and Glycophorin A expression on colonies, as assessed by FACS analysis.

The study concluded that inhibition of overexpressed mediator complex proteins offers a promising avenue to alleviate differentiation blocks in MDS/AML. This underscores a compelling rationale for advancing the development of the CDK8/19 inhibitor RVU120, particularly for transfusion-dependent MDS/AML patients.

The study is sponsored by Ryvu Therapeutics SA

Source: https://ash.confex.com/ash/2023/webprogram/Paper186227.html

Clinical Trial: https://clinicaltrials.gov/study/NCT04021368

Ajibade O, Pakulska U, Rabinovich E, et al. (2023). “Novel Clinically Useful Inhibitor of Mediator Complex, RVU120, Relives Differentiation Block in MDS/AML.” Presented at ASH 2023 (Abstract 3225).