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

  • J Med Chem. 2019 Jan 24;62(2):531-551. doi: 10.1021/acs.jmedchem.8b01085.
Takao Uno  1 ,  Yuichi Kawai  1 ,  Satoshi Yamashita  1 ,  Hiromi Oshiumi  2 ,  Chihoko Yoshimura  1 ,  Takashi Mizutani  1 ,  Tatsuya Suzuki  1 ,  Khoon Tee Chong  1 ,  Kazuhiko Shigeno  1 ,  Mitsuru Ohkubo  1 ,  Yasuo Kodama  1 ,  Hiromi Muraoka  1 ,  Kaoru Funabashi  1 ,  Koichi Takahashi  1 ,  Shuichi Ohkubo  1 ,  Makoto Kitade  3
Affiliations
  • 1. Discovery and Preclinical Research Division , Taiho Pharmaceutical Co. Ltd. , Tsukuba , Ibaraki 300-2611 , Japan.
  • 2. Formulation Research, CMC Division , Taiho Pharmaceutical Co. Ltd. , Kawauchi-cho, Tokushima 771-0194 , Japan.
  • 3. Chemical Technology Laboratory, CMC Division , Taiho Pharmaceutical Co. Ltd. , Kamikawa-machi, Kodama-gun, Saitama 367-0241 , Japan.
PMID: 30525599 DOI: 10.1021/acs.jmedchem.8b01085
Abstract

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)-1 H-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.