1260536-53-5Relevant articles and documents
Discovery of 3-Ethyl-4-(3-isopropyl-4-(4-(1-methyl-1 H-pyrazol-4-yl)-1 H-imidazol-1-yl)-1 H-pyrazolo[3,4- b]pyridin-1-yl)benzamide (TAS-116) as a Potent, Selective, and Orally Available HSP90 Inhibitor
Uno, Takao,Kawai, Yuichi,Yamashita, Satoshi,Oshiumi, Hiromi,Yoshimura, Chihoko,Mizutani, Takashi,Suzuki, Tatsuya,Chong, Khoon Tee,Shigeno, Kazuhiko,Ohkubo, Mitsuru,Kodama, Yasuo,Muraoka, Hiromi,Funabashi, Kaoru,Takahashi, Koichi,Ohkubo, Shuichi,Kitade, Makoto
supporting information, p. 531 - 551 (2019/01/08)
The molecular chaperone heat shock protein 90 (HSP90) is a promising target for cancer therapy, as it assists in the stabilization of cancer-related proteins, promoting cancer cell growth, and survival. A novel series of HSP90 inhibitors were discovered by structure-activity relationship (SAR)-based optimization of an initial hit compound 11a having a 4-(4-(quinolin-3-yl)-1H-indol-1-yl)benzamide structure. The pyrazolo[3,4-b]pyridine derivative, 16e (TAS-116), is a selective inhibitor of HSP90α and HSP90β among the HSP90 family proteins and exhibits oral availability in mice. The X-ray cocrystal structure of the 16e analogue 16d demonstrated a unique binding mode at the N-terminal ATP binding site. Oral administration of 16e demonstrated potent antitumor effects in an NCI-H1975 xenograft mouse model without significant body weight loss.
