CB-5339

CB-5339 is a second-generation, orally bioavailable, potent and selective small molecule inhibitor of valosin-containing protein (VCP), also known as p97. It acts as an ATP-competitive inhibitor of VCP/p97, disrupting its function in protein homeostasis and inducing proteotoxic stress in cancer cells. This leads to the accumulation of polyubiquitylated proteins, retention of ERAD substrates, activation of the unfolded protein response (UPR), and ultimately lethal endoplasmic reticulum (ER) stress mediated by CHOP, DR5, and NOXA. The drug was developed to improve upon first-generation inhibitors like CB-5083 by reducing off-target effects such as phosphodiesterase 6 inhibition while maintaining antitumor efficacy. Preclinical studies have shown activity against acute myeloid leukemia (AML), multiple myeloma, solid tumors, and high-risk myelodysplastic syndromes—including those with TP53 mutations or 3q26 lesions—by impairing DNA repair through ATM kinase signaling disruption. Clinical development has included phase 1/2 trials for hematologic malignancies and solid tumors[1][2][3][4][5][7].

Other names

p97 inhibitor CB-5339p-97 inhibitor CB-5339p 97 inhibitor CB-5339VCP/p97 inhibitor CB-5339