Abstract 4530: Synergistic targeting of Mediator complex and BCL-2 reveals a novel therapeutic strategy for acute myeloid leukemia

Abstract Background: Acute myeloid leukemia (AML) is a heterogeneous and aggressive hematologic malignancy characterized by the uncontrolled proliferation of myeloid stem and progenitor cells. Despite therapeutic advances, the 5-year survival rate remains low, underscoring the urgent need for novel therapeutic strategies. Methods: To meet this need and identify new anti-leukemic agents, we conducted a high-throughput cell viability screen of 10,000 small molecules using 56 different primary AML specimens of diverse genetic anomalies. Molecules showing highly correlated inhibition profiles were grouped into 21 compound correlation clusters (CCCs). The overall hypothesis was that compounds sharing highly correlated inhibition profiles most likely act on the same biological pathway / molecular target. Among the various CCC identified, CCC163, which include compound AML874, emerged as a potent and selective anti-leukemic hit. Results: Integrated pharmacological and CRISPR-Cas9 screening revealed the Mediator complex as the molecular target of AML874. Mechanistic studies confirmed that AML874 inhibits Mediator complex function through CDK8/CDK19 kinase inhibition, leading to transcriptional dysregulation and loss of Mediator structural integrity. Kinase-dead CDK8 rescue assays confirmed that AML874 activity depends on CDK8 kinase function. Notably, FLT3-mutated AML primary specimens exhibited increased sensitivity to AML874, indicating a potential subtype-specific therapeutic opportunity. Structure-activity relationship profiling of AML874 analogs further supported the dependency on Mediator complex disruption for anti-leukemic activity. Finally, combination studies demonstrated strong synergy between AML874 and the BCL2 inhibitor venetoclax both in vitro and in vivo, resulting in markedly improved anti-leukemic activity in xenograft models. Conclusions: This work identifies the Mediator complex as a novel vulnerability in AML and positions CDK8/CDK19 inhibition, alone or in combination with Venetoclax, as a promising strategy for the development of next-generation targeted therapies for this disease. Citation Format: Camille Aitchedji, Céline Moison, Deanne Gracias, Rodrigo Mendoza-Sanchez, Simon Fortier, Jean-François Spinella, Tara Macrae, Nadine Mayotte, Mélanie Frechette, Valérie Blouin-Chagnon, Koryne Leveillé, Réjean Ruel, Anne Marinier, Guy Sauvageau, Josée Hébert. Synergistic targeting of Mediator complex and BCL-2 reveals a novel therapeutic strategy for acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4530.