Article ; Online: 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.
Journal of medicinal chemistry
2018 Volume 62, Issue 2, Page(s) 531–551
Abstract: ... 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 ...
| 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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| MeSH term(s) | Administration, Oral ; Animals ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/metabolism ; Antineoplastic Agents/therapeutic use ; Benzamides/chemistry ; Benzamides/metabolism ; Benzamides/therapeutic use ; Binding Sites ; Cell Line, Tumor ; Crystallography, X-Ray ; Drug Design ; Drug Screening Assays, Antitumor ; HSP90 Heat-Shock Proteins/antagonists & inhibitors ; HSP90 Heat-Shock Proteins/genetics ; HSP90 Heat-Shock Proteins/metabolism ; Humans ; Mice ; Mice, Nude ; Molecular Conformation ; Molecular Dynamics Simulation ; Neoplasms/drug therapy ; Neoplasms/pathology ; Pyrazoles/chemistry ; Pyrazoles/metabolism ; Pyrazoles/therapeutic use ; Quinolines/chemistry ; Recombinant Proteins/biosynthesis ; Recombinant Proteins/chemistry ; Recombinant Proteins/isolation & purification ; Solubility ; Structure-Activity Relationship |
| Chemical Substances | Antineoplastic Agents ; Benzamides ; HSP90 Heat-Shock Proteins ; Pyrazoles ; Quinolines ; Recombinant Proteins ; TAS-116 ; quinoline (E66400VT9R) |
| Language | English |
| Publishing date | 2018-12-21 |
| Publishing country | United States |
| Document type | Journal Article |
| ZDB-ID | 218133-2 |
| ISSN | 1520-4804 ; 0022-2623 |
| ISSN (online) | 1520-4804 |
| ISSN | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.8b01085 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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