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Figure 2
Subtractive optimization strategy to develop a selective VCP/p97 inhibitor. (a) The chemical structure of CB-5083. The cyan-colored crescent adjacent to the pyran ring highlights the region that has close packing steric inter­actions in the PDE6 binding site, also highlighted by the red oval in Fig. 1[link](b). (b) The chemical structure of the scaffold used to generate com­pounds that were designed to retain VCP/p97 inhibition but unable to bind to PDE6, highlighting the two sites for functionalization by introducing different R1 and R2 groups. (c) Compound potency against VCP/p97 ATPase (IC50 in nM) and PDE6 activity (%Inhibition at 10 µM) for selected com­pounds shown alongside their chemical structures, where R1 and R2 refer to the structural sites marked in part (b), ultimately resulting in the GND-135 com­pound. IC50 values are represented as geomean from independent experiments (N ≥ 2) and %Inhibition as the mean of replicates (n = 2). (d) The chemical structure of GND-135. The green arrows mark the locations of some of the key inter­actions in the binding pocket including (1) the functionalization that sterically precludes PDE6 binding, (2) the removal of a hy­dro­gen-bond acceptor atom from the pyran ring in CB-5083 that contributes to PDE6 binding and (3, 4) sites that maintain strong polar inter­actions with nearby VCP/p97 residues, contributing to selective VCP/p97 inhibition. (e) VCP/p97 inhibition dose response curves for CB-5083 and GND-135. Data points are represented as mean ± SD for replicates (n = 3).

IUCrJ
Volume 13| Part 4| July 2026|
ISSN: 2052-2525
https://doi.org/10.1107/S2052252526004604