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TitleCryo-EM-guided subtractive optimization of a novel VCP/p97 inhibitor.
Journal, issue, pagesIUCrJ, Vol. 13, Issue Pt 4, Page 364-372, Year 2026
Publish dateJul 1, 2026
AuthorsJason Crawford / Ravi Munuganti / Charles Leung / Kriti Singh / Ellen Gates / Xing Zhu / Marcel Bally / Nancy Dos Santos / Maryam Sharifiaghdam / Zeynab Nosrati / Peter Axerio-Cilies / Alison M Berezuk / Spencer Cholak / Alan Merk / Dale R Cameron / Sriram Subramaniam /
PubMed AbstractWe 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 ...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.
External linksIUCrJ / PubMed:42329166 / PubMed Central
MethodsEM (single particle)
Resolution2.46 - 2.72 Å
Structure data

70500

9ohm

EMDB-70500, PDB-9ohm:
Cryo-EM structure of bovine phosphodiesterase 6 bound to CB-5083
Method: EM (single particle) / Resolution: 2.72 Å

70501

9ohn

EMDB-70501, PDB-9ohn:
Cryo-EM structure of human p97/VCP bound to inhibitor GND-135
Method: EM (single particle) / Resolution: 2.46 Å

Chemicals

ChemComp-PCG:
CYCLIC GUANOSINE MONOPHOSPHATE

ChemComp-ZN:
Unknown entry

ChemComp-MG:
Unknown entry

ChemComp-JDP:
1-[4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carboxamide

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

PDB-1cbf:
THE X-RAY STRUCTURE OF A COBALAMIN BIOSYNTHETIC ENZYME, COBALT PRECORRIN-4 METHYLTRANSFERASE, CBIF

Source
  • bos taurus (domestic cattle)
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN / GAF domain / phosphohydrolase / G protein-coupled receptor signaling / CB-5083 / HYDROLASE/HYDROLASE INHIBITOR / p97 / VCP / TERA / Inhibitor / GND-135 / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex

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