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Mediator kinase inhibition exposes a transcriptional vulnerability and primes AML for venetoclax sensitivity [CRISPR Screen]

ABSTRACT: Acute myeloid leukemia (AML) is a heterogeneous and aggressive hematologic malignancy associated with poor survival despite recent therapeutic advances. To identify novel anti-leukemic agents, we performed a high-throughput viability screen of 10,000 small molecules across 56 genetically diverse primary AML samples. Compounds with similar activity profiles were grouped into Compound Correlation Clusters (CCCs), leading to the identification of CCC163, which includes AML874, as a potent and selective hit. Integrated pharmacological and CRISPR-Cas9 approaches identified the Mediator complex as the molecular target of AML874. We demonstrate that AML874 acts as a selective CDK8/CDK19 inhibitor, disrupting Mediator-dependent transcription. FLT3-mutated AML showed increased sensitivity to AML874, suggesting a subtype-specific vulnerability. Notably, CDK8 inhibition synergized with venetoclax in AML cell lines and patient-derived xenograft models, resulting in enhanced anti-leukemic activity in vivo. Together, these findings identify AML874 as a promising therapeutic candidate and highlight CDK8/CDK19 inhibition as a potential strategy in AML.

ORGANISM(S): Homo sapiens

PROVIDER: GSE327914 | GEO | 2026/06/29

REPOSITORIES: GEO

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Project description:There is an unmet need for chemical tools to explore the role of the Mediator complex in human pathologies ranging from cancer to cardiovascular disease. Here we determine that CCT251545 a WNT-pathway inhibitor discovered by cell-based screening is a potent and selective chemical probe for the Mediator complex-associated protein kinases CDK8 and CDK19. CCT251545 is an ATP competitive inhibitor with >100-fold selectivity over 291 other kinases. X-ray crystallography demonstrates Type 1 binding involving insertion of the CDK8 C-terminus into the ligand binding site. In contrast to Type II inhibitors of CDK8/19 CCT251545 displays potent cell-based activity. We show that CCT251545 and close analogues not only alter WNT-pathway regulated gene expression but also other CDK8/19 targets including STAT1-regulated gene expression. Consistent with this we find that phospho-STAT1SER727 is a biomarker of CDK8 kinase activity in vitro and in vivo. Finally we demonstrate in vivo activity of CCT251545 in WNT-dependent tumours. Compound 1,2, 6 and 9 are close analogues of a 3,4,5-trisubstituted pyridine series identified from a high-throughput cell-based reporter assay of WNT signalling. They were shown to be potent and selective inhibitors of the Mediator complex-associated protein kinases CDK8 and CDK19. They are ATP competitive inhibitors with >100-fold selectivity over 291 other kinases. X-ray crystallography demonstrates Type 1 binding involving insertion of the CDK8 C-terminus into the ligand-binding site. A 3D culture model of murine intestinal-derived organoids expressing a transgenic doxycycline-inducible mutant beta-catenin expression following removal of doxycycline results in reduced WNT signalling and was compared to treatment for 24 hours with coumpound 2, 6 and 9. Compound 2 (n=3), compound 6 (n=4), compound 9 (n=3), doxycycline removal (n=4), doxycycline treatment (n=7). Samples were hybridized agianst mouse reference. Compounds 2, 6 and 9 are close analogues of a 3,4,5-trisubstituted pyridine series identified from a high-throughput cell-based reporter assay of WNT signalling. They were shown to be potent and selective inhibitors of the Mediator complex-associated protein kinases CDK8 and CDK19. They are ATP competitive inhibitors with >100-fold selectivity over 291 other kinases. X-ray crystallography demonstrates Type 1 binding involving insertion of the CDK8 C-terminus into the ligand-binding site.

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Mediator kinase inhibition exposes a transcriptional vulnerability and primes AML for venetoclax sensitivity [CRISPR Screen]

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