1018974-87-2Relevant 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.
NOVEL PYRIMIDINE DERIVATIVES, PREPARATION THEREOF, AND PHARMACEUTICAL USE THEREOF AS AKT(PKB) PHOSPHORYLATION INHIBITORS
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Paragraph 2946-2947, (2013/10/22)
The present invention relates to novel chemical compounds derived from pyrimidines, to the method for preparing same, to the novel intermediates obtained, to the use thereof as drugs, to the pharmaceutical compositions containing same, and to the therapeutic use thereof as AKT inhibitors.
INDOLE SULFONAMIDES AS SFRP-1 MODULATORS
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Page/Page column 36, (2008/12/05)
Indole sulfonamide compounds or pharmaceutically acceptable salts thereof, are provided, which are modulators of secreted frizzled related protein-1. The compounds, and compositions containing the compounds, can be used to treat a variety of disorders, in
