5ZR3

Crystal structure of Hsp90-alpha N-terminal domain in complex with 4-(3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)-3-methylbenzamide

Summary for 5ZR3

• Entry DOI: 10.2210/pdb5zr3/pdb
• Descriptor: Heat shock protein HSP 90-alpha, 3-methyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide (3 entities in total)
• Functional Keywords: inhibitor, complex, chaperone
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 108721.69

Authors

Uno, T.,Chong, K.T.,Suzuki, T. (deposition date: 2018-04-23, release date: 2019-01-02, Last modification date: 2023-11-22)

Primary citation

Uno, T.,Kawai, Y.,Yamashita, S.,Oshiumi, H.,Yoshimura, C.,Mizutani, T.,Suzuki, T.,Chong, K.T.,Shigeno, K.,Ohkubo, M.,Kodama, Y.,Muraoka, H.,Funabashi, K.,Takahashi, K.,Ohkubo, S.,Kitade, M.
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., 62:531-551, 2019

PubMed 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.

PubMed: 30525599
DOI: 10.1021/acs.jmedchem.8b01085

Experimental method

X-RAY DIFFRACTION (2.5 Å)