1260539-02-3Relevant articles and documents
Thermodynamic Dissection of Potency and Selectivity of Cytosolic Hsp90 Inhibitors
Yoshimura, Chihoko,Nagatoishi, Satoru,Kuroda, Daisuke,Kodama, Yasuo,Uno, Takao,Kitade, Makoto,Chong-Takata, Khoontee,Oshiumi, Hiromi,Muraoka, Hiromi,Yamashita, Satoshi,Kawai, Yuichi,Ohkubo, Shuichi,Tsumoto, Kouhei
, p. 2669 - 2677 (2021)
The cytosolic Hsp90-selective inhibitor TAS-116 has an acceptable safety profile and promising antitumor activity in clinical trials. We examined the binding characteristics of TAS-116 and its analogs to determine the impact of the ligand binding mode on selectivity for cytosolic Hsp90. Analyses of the co-crystal structure of Hsp90 and inhibitor TAS-116 suggest that TAS-116 interacts with the ATP-binding pocket, the ATP lid region, and the hydrophobic pocket. A competitive isothermal titration calorimetry analysis confirmed that a small fragment of TAS-116 (THS-510) docks into the lid region and hydrophobic pockets without binding to the ATP-binding pocket. THS-510 exhibited enthalpy-driven binding to Hsp90α and selectively inhibited cytosolic Hsp90 activity. The heat capacity change of THS-510 binding was positive, likely due to the induced conformational rearrangement of Hsp90. Thus, we concluded that interactions with the hydrophobic pocket of Hsp90 determine potency and selectivity of TAS-116 and derivatives for the cytosolic Hsp90 isoform.
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
, 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.
AZABICYCLO COMPOUND AND SALT THEREOF
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Page/Page column 44, (2012/05/07)
It is intended to provide a novel azabicyclo compound which exhibits both HSP90 inhibitory activity and cell proliferation inhibitory effect. Specifically disclosed is a compound represented by the following general formula (I) or a salt thereof: wherein X1 represents CH or N; any one of X2, X3 and X4 represents N, and the others represent CH; any one or two of Y1, Y2, Y3 and Y4 represent C—R4, and the others are the same or different and represent CH or N; R1 represents an optionally substituted monocyclic or bicyclic unsaturated heterocyclic group having 1 to 4 heteroatoms selected from N, S and O; R2 represents an alkyl group having 1 to 6 carbon atoms, or the like; and R3 and R4 represent —CO—R5 or the like.
