Discovery of potent CDK8/CDK19 PROTAC degraders with superior anti-leukemia efficacy

Aggressive leukemias, including acute myeloid leukemia (AML), remain highly challenging diseases due to the lack of curative therapies. AML rapidly develops resistance to both conventional and targeted treatments, underscoring the urgent need for more effective therapeutic strategies. Recently, the transcription-regulating Mediator kinases CDK8 and CDK19 have emerged as promising targets, with CDK8/19 kinase inhibitors (CDK8/19i) now in clinical trials for leukemia. However, preliminary data from our laboratory demonstrate that leukemia cell lines exhibit heterogeneous and often incomplete responses to CDK8/19i, with many developing resistance after initial sensitivity. To test the hypothesis that direct depletion of CDK8/19 proteins in contrast to inhibiting kinase activity alone, may elicit more potent and durable anti-leukemia activity, we developed three series of PROteolysis TArgeting Chimeras (PROTACs) based on selective CDK8/19 inhibitors conjugated through diverse linkers to cereblon (CRBN)-recruiting ligands. After extensive optimization of both the kinase targeted warhead and composition of the linker, the most potent degrader obtained, SNX7886, induced efficient and simultaneous degradation of CDK8 and CDK19 across multiple cell types with a DC 50 of 10 nM. When evaluated side-by-side with its cognate CDK8/19i (BI1347), SNX7886 consistently produced superior and sustained growth inhibition without the adaptive resistance observed with CDK8/19 kinase inhibitors in multiple leukemia lines. Notably, in an aggressive refractory AML cell line NOMO1, prolonged treatment with CDK8/19-PROTACs resulted in complete growth arrest, with no surviving cells detectable over extended exposure. Transcriptomic and proteomic analyses further revealed that CDK8/19-PROTACs engage both shared and distinct molecular pathways compared to CDK8/19i, indicating deeper disruption of transcriptional reprogramming circuits associated with AML survival and adaptation. These findings highlight targeted CDK8/19 degradation as a promising therapeutic strategy capable of overcoming key limitations of CDK8/19 kinase inhibitors in AML.