Fig. 7

Chemical CDK8 degradation cooperates with mTOR inhibition. a Co-expression matrix of CDK8 and members of mTOR/PI3K signaling pathways in samples of 203 pediatric ALL patients (TARGET cohort, RNA-seq) and b 179 AML patients (TCGA AML cohort, RNA-seq). The scale indicates Spearman’s correlation coefficients ranging from −1 (red) to 1 (blue). c Structure of degrader YKL-06-101 and biochemically verified IC₅₀’s for mTOR and CDK8/Cyclin C inhibition. d Thymidine incorporation assay based IC₅₀’s of BCR-ABL1⁺ (BV173, Nalm1, Tom1, Z119) and BCR-ABL1⁻ (BL41, Raji, Ramos, REH) human leukemic cell lines after 48 h incubation with increasing concentrations of JH-XI-10-02, YKL-06-101, or Senexin B. e AnnexinV/7AAD staining of REH cells incubated with 0.5 µM and 1 µM of JH-XI-10-02 or YKL-06-101 for 72 and 96 h. DMSO was used as vehicle control (D: DMSO, n = 3). Immunoblots show mTOR, CDK8, and pS6 after incubation of f REH cells or g Z119 cells with 0.5 µM and 1 µM of JH-XI-10-02 or YKL-06-101 for 48, 72, and 96 h. DMSO (indicated as D) was used as vehicle control and β-actin served as loading control. h AnnexinV/7AAD staining of Z119 cells incubated with 0.5 µM and 1 µM of JH-XI-10-02 or YKL-06-101 for 72 and 96 h. DMSO was used as a vehicle control (D: DMSO, n = 3). i AnnexinV/7AAD staining of Z119 cells incubated with Torin1, JH-XI-10-02, or both in combination with indicated concentrations for 72 and 96 h. DMSO (indicated as D) was used as a vehicle control. One representative experiment out of three is depicted. j Bar diagram depicts relative thymidine incorporation of six primary B-ALL patient samples incubated for 48 h with 1 μM of YKL-06-101. Patient #1 represents a non-responder, patient #4 was BCR-ABL1⁺ (Ph⁺), whereas the others were BCR-ABL1⁻ (Ph⁻). Levels of significance were calculated using Kruskal–Wallis test followed by Dunn’s test, data represents means ± SD (*p < 0.05, **p < 0.01). Source data are provided as a Source Data file