title: Small molecule screen for inhibitors of expression from canonical CREB response element-containing promoters.
abstract: The transcription factor CREB (cAMP Response Element Binding Protein) is an important determinant in the growth of Acute Myeloid Leukemia (AML) cells. CREB overexpression increases AML cell growth by driving the expression of key regulators of apoptosis and the cell cycle. Conversely, CREB knockdown inhibits proliferation and survival of AML cells but not normal hematopoietic cells. Thus, CREB represents a promising drug target for the treatment of AML, which carries a poor prognosis. In this study, we performed a high-throughput small molecule screen to identify compounds that disrupt CREB function in AML cells. We screened ~114,000 candidate compounds from Stanford University's small molecule library, and identified 5 molecules that inhibit CREB function at micromolar concentrations, but are non-toxic to normal hematopoietic cells. This study suggests that targeting CREB function using small molecules could provide alternative approaches to treat AML.
authors: Department of Pediatrics, Stanford University, Stanford, CA, USA.
authors: Bryan
authors: B
authors: Mitton
authors: Department of Pediatrics, Stanford University, Stanford, CA, USA.
authors: Katie
authors: K
authors: Hsu
authors: Department of Pediatrics, Stanford University, Stanford, CA, USA.
authors: Ritika
authors: R
authors: Dutta
authors: Department of Pediatrics, Stanford University, Stanford, CA, USA.
authors: Bruce C
authors: BC
authors: Tiu
authors: Medicinal Chemistry Knowledge Center, Stanford ChEM-H, Stanford, CA, USA.
authors: Nick
authors: N
authors: Cox
authors: Department of Pediatrics, Stanford University, Stanford, CA, USA.
authors: Kevin G
authors: KG
authors: McLure
authors: Department of Pediatrics, Stanford University, Stanford, CA, USA.
authors: Hee-Don
authors: HD
authors: Chae
authors: Medicinal Chemistry Knowledge Center, Stanford ChEM-H, Stanford, CA, USA.
authors: Mark
authors: M
authors: Smith
authors: Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors: Elizabeth A
authors: EA
authors: Eklund
authors: High-Throughput Bioscience Center, Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.
authors: David E
authors: DE
authors: Solow-Cordero
authors: Department of Pediatrics, Stanford University, Stanford, CA, USA.
authors: Kathleen M
authors: KM
authors: Sakamoto
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D008156:Luciferases / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020218:Response Elements / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D012333:RNA, Messenger; D054852:Small Molecule Libraries; D008156:Luciferases
keywords: CREB; novel therapeutics; small molecule screen