Article ; Online: SAR optimization studies on modified salicylamides as a potential treatment for acute myeloid leukemia through inhibition of the CREB pathway.
Bioorganic & medicinal chemistry letters
2019 Volume 29, Issue 16, Page(s) 2307–2315
Abstract: Disruption of cyclic adenosine monophosphate response element binding protein (CREB) provides a potential new strategy to address acute leukemia, a disease associated with poor prognosis, and for which conventional treatment options often carry a ... ...
| Abstract | Disruption of cyclic adenosine monophosphate response element binding protein (CREB) provides a potential new strategy to address acute leukemia, a disease associated with poor prognosis, and for which conventional treatment options often carry a significant risk of morbidity and mortality. We describe the structure-activity relationships (SAR) for a series of XX-650-23 derived from naphthol AS-E phosphate that disrupts binding and activation of CREB by the CREB-binding protein (CBP). Through the development of this series, we identified several salicylamides that are potent inhibitors of acute leukemia cell viability through inhibition of CREB-CBP interaction. Among them, a biphenyl salicylamide, compound 71, was identified as a potent inhibitor of CREB-CBP interaction with improved physicochemical properties relative to previously described derivatives of naphthol AS-E phosphate. |
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| MeSH term(s) | Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; CREB-Binding Protein/antagonists & inhibitors ; CREB-Binding Protein/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; HL-60 Cells ; Humans ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/metabolism ; Molecular Structure ; Salicylamides/chemical synthesis ; Salicylamides/chemistry ; Salicylamides/pharmacology ; Structure-Activity Relationship |
| Chemical Substances | Antineoplastic Agents ; Enzyme Inhibitors ; Salicylamides ; CREB-Binding Protein (EC 2.3.1.48) ; CREBBP protein, human (EC 2.3.1.48) |
| Language | English |
| Publishing date | 2019-06-19 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 1063195-1 |
| ISSN | 1464-3405 ; 0960-894X |
| ISSN (online) | 1464-3405 |
| ISSN | 0960-894X |
| DOI | 10.1016/j.bmcl.2019.06.023 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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