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

Hee-Don Chae; Nick Cox; Samanta Capolicchio; Jae Wook Lee; Naoki Horikoshi; Sharon Kam; Andrew A Ng; Jeffrey Edwards; Tae-León Butler; Justin Chan; Yvonne Lee; Garrett Potter; Mark C Capece; Corey W Liu; Soichi Wakatsuki; Mark Smith; Kathleen M Sakamoto

doi:10.1016/j.bmcl.2019.06.023

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. Epub 2019 Jun 19.

Authors

Hee-Don Chae¹, Nick Cox², Samanta Capolicchio³, Jae Wook Lee¹, Naoki Horikoshi⁴, Sharon Kam¹, Andrew A Ng³, Jeffrey Edwards¹, Tae-León Butler¹, Justin Chan¹, Yvonne Lee¹, Garrett Potter³, Mark C Capece⁵, Corey W Liu⁶, Soichi Wakatsuki⁷, Mark Smith⁸, Kathleen M Sakamoto⁹

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
CREB-Binding Protein / antagonists & inhibitors*
CREB-Binding Protein / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
HL-60 Cells
Humans
Leukemia, Myeloid, Acute / drug therapy*
Leukemia, Myeloid, Acute / metabolism
Molecular Structure
Salicylamides / chemical synthesis
Salicylamides / chemistry
Salicylamides / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Enzyme Inhibitors
Salicylamides
CREB-Binding Protein
CREBBP protein, human