5zr3
From Proteopedia
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
Structural highlights
Function[HS90A_HUMAN] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function.[1] [2] Publication Abstract from PubMedThe 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 HSP90alpha and HSP90beta among the HSP90 family proteins and exhibits oral availability in mice. X-ray co-crystal structure of the 16e analog 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. 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 T, Kawai Y, Yamashita S, Oshiumi H, Yoshimura C, Mizutani T, Suzuki T, Chong KT, Shigeno K, Ohkubo M, Kodama Y, Muraoka H, Funabashi K, Takahashi K, Ohkubo S, Kitade M J Med Chem. 2018 Dec 7. doi: 10.1021/acs.jmedchem.8b01085. PMID:30525599[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Chong, K T | Suzuki, T | Uno, T | Chaperone | Complex | Inhibitor
