Figure 3 |. Ligase and linker influences degrader selectivity.

(A) Chemical structures for dacinostat-based CRBN/VHL1/VHL2/IAP matched series of degraders (PEG2). (B) In vitro inhibition of HDAC enzymatic activity (pIC₅₀) for the degraders in A. Inhibition data is from n = 1 ten-point titrations. (C) Heatmap displaying the log₂FC in relative abundance for quantified HDACs in response to treatment with degraders in A. (D) Scatterplot comparing HDAC engagement B with HDAC degradation C for the matched degraders in A. (E) Chemical structures for two SAHA-based CRBN/VHL1 matched pairs of degraders. (F) Scatterplot comparing HDAC degradation (log₂FC) for degraders in E. (G) Chemical structures for two dacinostat-based CRBN/VHL1 matched pairs of degraders. (H) Scatterplot comparing HDAC degradation (log₂FC) for degraders in G. (I) Heatmap displaying the log₂FC in relative abundance for quantified HDACs in response to indicated degraders assessing linker length. (J) Chemical structures for VHL1 or VHL2-based degraders. (K) Heatmap displaying the log₂FC in relative abundance for quantified HDACs in response to indicated degraders. Proteomics data is from n = 1–2 biological replicates. * on proteomics heatmaps indicates a P-value < 0.001. See also Table S2–3, Figure S1, S3, S4.