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

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• 作者：Han-Jie Zhou ; Jinhai Wang ; Bing Yao ; Steve Wong ; Stevan Djakovic ; Brajesh Kumar ; Julie Rice ; Eduardo Valle ; Ferdie Soriano ; Mary-Kamala Menon ; Antonett Madriaga ; Szerenke Kiss von Soly ; Abhinav Kumar ; Francesco Parlati ; F. Michael Yakes ; Laura Shawver ; Ronan Le Moigne ; Daniel J. Anderson ; Mark Rolfe ; David Wustrow
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：December 24, 2015
• 年：2015
• 卷：58
• 期：24
• 页码：9480-9497
• 全文大小：907K
• ISSN：1520-4804

文摘

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.