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Title: SAR optimization studies on modified salicylamides as a potential treatment for acute myeloid leukemia through inhibition of the CREB pathway

Journal Article · · Bioorganic and Medicinal Chemistry Letters
 [1];  [2];  [2];  [1];  [3];  [1]; ORCiD logo [2];  [1];  [1];  [1];  [1]; ORCiD logo [2];  [4];  [5];  [6];  [2];  [1]
  1. Stanford Univ. School of Medicine, Stanford, CA (United States)
  2. Medicinal Chemistry Knowledge Center, Stanford, CA (United States)
  3. Stanford Univ. School of Medicine, Stanford, CA (United States); Univ. of Tsukuba (Japan)
  4. Stanford Univ., CA (United States)
  5. Macromolecular Structure Knowledge Center, Stanford, CA (United States)
  6. Stanford Univ. School of Medicine, Stanford, CA (United States); SLAC National Accelerator Lab., Menlo Park, CA (United States)
+ Show Author Affiliations

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. In this paper, 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.

Research Organization:
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
Sponsoring Organization:
USDOE
Grant/Contract Number:
AC02-76SF00515
OSTI ID:
1560676
Journal Information:
Bioorganic and Medicinal Chemistry Letters, Vol. 29, Issue 16; ISSN 0960-894X
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
English

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Figures / Tables (16)

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
60 APPLIED LIFE SCIENCES
Salicylamide
Acute myeloid leukemia
Small molecule
CREB
CBP