CB-5083

CB‑5083 is a first-in-class, orally bioavailable small molecule inhibitor of the valosin-containing protein (VCP), also known as p97. VCP/p97 is a type II AAA ATPase that plays a central role in cellular protein homeostasis by mediating ubiquitin-dependent protein degradation and endoplasmic reticulum-associated degradation (ERAD). By selectively inhibiting the D2 ATPase domain of p97, CB‑5083 disrupts these processes, leading to accumulation of polyubiquitinated proteins and activation of the unfolded protein response. This results in apoptosis and inhibition of cell proliferation in susceptible tumor cells. Preclinical studies demonstrated antitumor activity across multiple hematologic malignancies and solid tumors. Clinical development was initiated for cancer indications but phase I trials were terminated due to adverse visual effects attributed to off-target inhibition of phosphodiesterase 6 (PDE6). Lower doses are being explored for genetic diseases such as inclusion body myopathy associated with VCP mutations[1][5][6][8].

Other names

1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(7,8-Dihydro-4-(phenylmethyl)amino)-5H-pyrano(4,3-d)pyrimidin-2-yl)-2-methyl-1H-indole–4-carboxamide