GND-135

GND-135 is a potent and selective small molecule inhibitor of the AAA ATPase p97 (also known as valosin-containing protein, VCP), developed by Gandeeva Therapeutics. It was designed using cryo-EM-guided rational drug design to overcome the off-target phosphodiesterase 6 (PDE6) inhibition associated with earlier p97 inhibitors like CB-5083, which led to clinical trial terminations due to ocular side effects. GND-135 demonstrates high potency with an IC50 of 3 nM for p97 ATPase inhibition and exhibits significantly reduced PDE6 activity (< 1% inhibition at 10 μM). Preclinical studies in mouse models of acute myeloid leukemia (AML) and multiple myeloma have shown efficacy comparable to CB-5083 with a suitable pharmacokinetic profile for daily administration. It is being investigated for the treatment of cancers characterized by proteotoxic stress and protein homeostasis imbalances.