1354699-91-4Relevant academic research and scientific papers
Discovery of a First-in-Class, Potent, Selective, and Orally Bioavailable Inhibitor of the p97 AAA ATPase (CB-5083)
Zhou, Han-Jie,Wang, Jinhai,Yao, Bing,Wong, Steve,Djakovic, Stevan,Kumar, Brajesh,Rice, Julie,Valle, Eduardo,Soriano, Ferdie,Menon, Mary-Kamala,Madriaga, Antonett,Kiss Von Soly, Szerenke,Kumar, Abhinav,Parlati, Francesco,Yakes, F. Michael,Shawver, Laura,Le Moigne, Ronan,Anderson, Daniel J.,Rolfe, Mark,Wustrow, David
, p. 9480 - 9497 (2016/01/12)
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.
Surprising repair activities of nonpolar analogs of 8-oxoG expose features of recognition and catalysis by base excision repair glycosylases
McKibbin, Paige L.,Kobori, Akio,Taniguchi, Yosuke,Kool, Eric T.,David, Sheila S.
supporting information; experimental part, p. 1653 - 1661 (2012/03/12)
Repair glycosylases locate and excise damaged bases from DNA, playing central roles in preservation of the genome and prevention of disease. Two key glycosylases, Fpg and hOGG1, function to remove the mutagenic oxidized base 8-oxoG (OG) from DNA. To inves
