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Cryo-EM-guided subtractive optimization of a novel VCP/p97 inhibitor
Jason Crawford1, Ravi Munuganti1, Charles Leung1
1Gandeeva Therapeutics Inc., Burnaby, BC, Canada.
Iucrj
|June 22, 2026
Summary
Researchers discovered GND-135, a novel inhibitor targeting the VCP/p97 AAA ATPase enzyme. This small molecule overcomes off-target effects seen in earlier drugs, demonstrating improved specificity and efficacy in preclinical models.
Area of Science:
- Biochemistry
- Structural Biology
- Drug Discovery
Background:
- The VCP/p97 AAA ATPase is a therapeutic target, but inhibitors like CB-5083 have shown off-target activity against PDE6.
- Cryo-electron microscopy (cryo-EM) provides high-resolution structural insights into drug-target interactions.
Purpose of the Study:
- To discover and design a novel small-molecule inhibitor of VCP/p97 with improved specificity.
- To overcome the off-target liabilities of existing VCP/p97 inhibitors using structural information.
Main Methods:
- Cryo-EM structural analysis of CB-5083 bound to VCP/p97 and PDE6.
- Structure-guided rational design of a new inhibitor, GND-135.
- Biochemical, cellular, and pharmacokinetic assays to evaluate GND-135 efficacy and specificity.
- In vivo testing in a mouse model of acute myeloid leukemia.
Main Results:
- GND-135 efficiently inhibits VCP/p97 in biochemical and cellular assays.
- GND-135 demonstrates favorable pharmacokinetics and tumor efficacy in a preclinical AML model.
- Structural analysis revealed key interactions enabling the design of a VCP/p97-specific inhibitor, eliminating PDE6 off-target activity.
Conclusions:
- Cryo-EM structure-guided design, termed 'subtractive optimization,' successfully yielded GND-135, a selective VCP/p97 inhibitor.
- This approach of leveraging on-target and off-target structures can accelerate targeted small-molecule drug discovery.
