9OHN

Cryo-EM structure of human p97/VCP bound to inhibitor GND-135

This is a non-PDB format compatible entry.

Summary for 9OHN

• Entry DOI: 10.2210/pdb9ohn/pdb
• EMDB information: 70501
• Descriptor: Transitional endoplasmic reticulum ATPase, ADENOSINE-5'-DIPHOSPHATE, (1P)-1-{4-(benzylamino)-2-methyl-1-[2-(morpholin-4-yl)-2-oxoethyl]-1H-pyrrolo[2,3-b]pyridin-6-yl}-2-methyl-1H-indole-4-carboxamide (3 entities in total)
• Functional Keywords: p97, vcp, tera, inhibitor, gnd-135, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 12
• Total formula weight: 1106117.12

Authors

Crawford, J.,Munuganti, R.,Leung, C.,Singh, K.,Gates, E.,Zhu, X.,Bally, M.,Dos Santos, N.,Sharifiaghdam, M.,Nosrati, Z.,Axerio-Cilies, P.,Berezuk, A.,Cholak, S.,Cameron, D.,Subramaniam, S. (deposition date: 2025-05-05, release date: 2026-05-27, Last modification date: 2026-07-22)

Primary citation

Crawford, J.,Munuganti, R.,Leung, C.,Singh, K.,Gates, E.,Zhu, X.,Bally, M.,Santos, N.D.,Sharifiaghdam, M.,Nosrati, Z.,Axerio-Cilies, P.,Berezuk, A.M.,Cholak, S.,Merk, A.,Cameron, D.R.,Subramaniam, S.
Cryo-EM-guided subtractive optimization of a novel VCP/p97 inhibitor.
Iucrj, 13:364-372, 2026

PubMed Abstract: We report the cryo-EM structure-guided discovery of GND-135, a novel small-molecule inhibitor of the VCP/p97 AAA ATPase that demonstrates efficient inhibition of VCP/p97 in biochemical, cellular, and pharmacokinetic assays and in a tumor efficacy mouse model of acute myeloid leukemia. Our approach overcomes the liability in the clinical-stage compound CB-5083 where Phase I studies showed off-target activity of CB-5083 for the enzyme PDE6. From the cryo-EM structural analysis of CB-5083 bound to PDE6 and VCP/p97, we identified critical ligand/protein interactions in both proteins and rationally designed a small molecule that retains key interactions necessary for VCP/p97 inhibition while eliminating PDE6 off-target activity. We refer to this approach as `subtractive optimization' because we are leveraging our ability to determine both on-target and off-target cryo-EM structures to guide the medicinal chemistry campaign to enable more targeted compound design. While this strategy is not possible in all cases, the use of cryo-EM to tune on-site binding while eliminating off-target binding could be a generally applicable strategy for informing molecular design and accelerating small-molecule drug discovery.

PubMed: 42329166
DOI: 10.1107/S2052252526004604

Experimental method

ELECTRON MICROSCOPY (2.46 Å)