Discovery of a First-in-Class, Potent, Selective, and Orally Bioavailable Inhibitor of the p97 AAA ATPase (CB-5083)

The AAA-ATPase p97 plays vital roles
in mechanisms of protein homeostasis,
including ubiquitin–proteasome system (UPS) mediated protein
degradation, endoplasmic reticulum-associated degradation (ERAD),
and autophagy. Herein we describe our lead optimization efforts focused
on in vitro potency, ADME, and pharmaceutical
properties that led to the discovery of a potent, ATP-competitive,
D2-selective, and orally bioavailable p97 inhibitor 71, CB-5083. Treatment of tumor cells with 71 leads to
significant accumulation of markers associated with inhibition of
UPS and ERAD functions, which induces irresolvable proteotoxic stress
and cell death. In tumor bearing mice, oral administration of 71 causes rapid accumulation of markers of the unfolded protein
response (UPR) and subsequently induces apoptosis leading to sustained
antitumor activity in in vivo xenograft models of both solid and hematological
tumors. 71 has been taken into phase 1 clinical trials
in patients with multiple myeloma and solid tumors.