Fig. 1: Cyclin A/B RxL inhibitors induce apoptosis in cancer cells with high E2F activity.

a, The structure of cyclin A (PDB: 1JSU), coloured by surface charge (blue, basic; red, acidic; white, neutral). HP, hydrophobic patch; S, the smaller adjacent hydrophobic pocket. b, The biochemical activity of cyclin RxL macrocycles against cyclin A1–CDK2, cyclin E1–CDK2 and cyclin B–CDK1 complexes was measured using fluorescence polarization. c, Docked model of CIRc-004 (green) bound to cyclin A and a detailed stick representation. d, GI₅₀ (concentrations resulting in 50% growth inhibition) waterfall plot of CIRc-004 in 46 human SCLC cell lines. e, Hallmark pathways associated with CIRc-004 sensitivity (false discovery rate (FDR) < 0.05) in 42 SCLC cell lines, calculated by GSVA using MSigDb Hallmark RNA-seq data (left). Cell lines were ranked by GI₅₀. Each column represents a distinct SCLC cell line, ranked from most to least sensitive. Right, comparison of CIRc-004 GI₅₀ values between high versus low E2F targets or G2M pathway groups (threshold, median pathway score; Mann–Whitney t-test). Alt., altered; non-alt, non-altered. f, Dose–response curves of the indicated SCLC (NCI-H1048, NCI-H446, NCI-H69, NCI-H82), NSCLC (A549, HCC4006, NCI-H1299) and human non-transformed RPE1 cell lines treated with CIRc-004 for 6 days. The average EC₅₀ values are shown. The arrows indicate DMSO controls (used for normalization). g, Representative flow cytometry plots of cleaved PARP in NCI-H1048 cells treated with CIRc-004 (200 nM) or DMSO for 3 days. h, Flow cytometry quantification of cleaved-PARP-positive cells after 3 days of CIRc-004 treatment. i, The cell cycle distribution after 24 h treatment with CIRc-004 or DMSO followed by propidium iodide staining. For f, h and i, n = 3 biological replicates. Data are mean ± s.d. Statistical significance in h was determined using unpaired two-tailed Student’s t-tests; *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

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