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
  • 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: [email protected].
  • 9. Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: [email protected].
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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