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Bioorg Med Chem Lett. 2019 Aug 15;29(16):2307-2315. doi: 10.1016/j.bmcl.2019.06.023. Epub 2019 Jun 19.

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

Author information

1
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
2
Medicinal Chemistry Knowledge Center, Stanford ChEM-H, Stanford, CA, USA; Presently at Novo Nordisk Research Center Seattle, Inc., USA.
3
Medicinal Chemistry Knowledge Center, Stanford ChEM-H, Stanford, CA, USA.
4
Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA; Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
5
Department of Chemistry, Stanford University, Stanford, CA, USA.
6
Macromolecular Structure Knowledge Center, Stanford ChEM-H, Stanford, CA, USA.
7
Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA; BioSciences Division, SLAC National Accelerator Laboratory, Menlo Park, CA, USA.
8
Medicinal Chemistry Knowledge Center, Stanford ChEM-H, Stanford, CA, USA. Electronic address: mxsmith@stanford.edu.
9
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: kmsakamo@stanford.edu.

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.

KEYWORDS:

Acute myeloid leukemia; CBP; CREB; Salicylamide; Small molecule

PMID:
31253529
DOI:
10.1016/j.bmcl.2019.06.023

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