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

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

  • Bioorg Med Chem Lett. 2019 Aug 15;29(16):2307-2315. doi: 10.1016/j.bmcl.2019.06.023.
Hee-Don Chae 1,  Nick Cox 2,  Samanta Capolicchio 3,  Jae Wook Lee 1,  Naoki Horikoshi 4,  Sharon Kam 1,  Andrew A Ng 3,  Jeffrey Edwards 1,  Tae-León Butler 1,  Justin Chan 1,  Yvonne Lee 1,  Garrett Potter 3,  Mark C Capece 5,  Corey W Liu 6,  Soichi Wakatsuki 7,  Mark Smith 8,  Kathleen M Sakamoto 9
Affiliations

Affiliations

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

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