2. Academic Validation
  3. 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

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

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.

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