- SAR optimization studies on modified salicylamides as a potential treatment for acute myeloid leukemia through inhibition of the CREB pathway
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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.
- Chae, Hee-Don,Cox, Nick,Capolicchio, Samanta,Lee, Jae Wook,Horikoshi,Kam, Sharon,Ng, Andrew A.,Edwards, Jeffrey,Butler, Tae-León,Chan, Justin,Lee, Yvonne,Potter, Garrett,Capece, Mark C.,Liu, Corey W.,Wakatsuki, Soichi,Smith, Mark,Sakamoto, Kathleen M.
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supporting information
p. 2307 - 2315
(2019/06/27)
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- INHIBITORS OF CREB-CBP INTERACTION FOR TREATMENT OF LEUKEMIA
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Compounds and methods are provided for inhibiting a CREB-CBP protein-protein interaction in a sample. In some cases, the method includes modulating transcription of CREB in a cell that overexpresses CREB. Also provided are methods of inhibiting the proliferation of a cancer cell. The subject CREB transcription inhibitor compounds include a substituted salicylamide or a prodrug thereof. Methods of alleviating symptoms associated with cancer (e.g., Acute Myeloid Leukemia (AML) or Acute Lymphomblastic Leukemia (ALL)) in a subject in need thereof are also provided. Pharmaceutical compositions including the subject compounds find use in treating cancer. The subject compounds may be formulated or provided to a subject in combination with a second agent, e.g. an anticancer agent.
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Page/Page column 40; 41
(2017/10/06)
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- 8-hydroxy-7-substituted quinolines as anti-viral agents
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The present invention provides for 8-hydroxy-7-substituted quinoline compounds such as formula III These compounds are useful as anti-viral agents. Specifically, these compounds have anti-viral activity against the herpes virus, cytomegalovirus (CMV). Many of these compounds are also active against other herpes viruses, such as the varicella zoster virus, the Epstein-Barr virus, the herpes simplex virus and the human herpes virus type 8 (HHV-8).
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