Small molecule screen for inhibitors of expression from canonical CREB response element-containing promoters
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Bryan Mitton1, Katie Hsu1, Ritika Dutta1, Bruce C. Tiu1, Nick Cox2, Kevin G. McLure1, Hee-Don Chae1, Mark Smith2, Elizabeth A. Eklund3, David E. Solow-Cordero4,*, Kathleen M. Sakamoto1,*
1Department of Pediatrics, Stanford University, Stanford, CA, USA
2Medicinal Chemistry Knowledge Center, Stanford ChEM-H, Stanford, CA, USA
3Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
4High-Throughput Bioscience Center, Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA
*These authors have contributed equally and share senior authorship
Kathleen M. Sakamoto, e-mail: [email protected]
Keywords: small molecule screen, novel therapeutics, CREB
Received: September 25, 2015 Accepted: January 13, 2016 Published: January 30, 2016
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.
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