Journal
CHEMISTRY & BIOLOGY
Volume 20, Issue 5, Pages 713-725Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2013.03.020
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Funding
- Friends for Life Fellowship
- Claudia Adams Barr Program in Cancer Research
- Howard Hughes Medical Institute Physician-Scientist Early Career Award
- National Cancer Institute's Initiative for Chemical Genetics, National Institutes of Health (NIH) [N01-CO-12400]
- NIGMS [P50 GM069721]
- NIH [RL1CA133834, RL1HG004671, RL1GM084437, UL1DE019585]
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While cytotoxic chemotherapy remains the hallmark of cancer treatment, intensive regimens fall short in many malignancies, including high-risk neuroblastoma. One alternative. strategy is to therapeutically promote tumor differentiation. We created a gene expression signature to measure neuroblast maturation, adapted it to a high-throughput platform, and screened a diversity oriented synthesis-generated small-molecule library for differentiation inducers. We identified BRD8430, containing a nine-membered lactam, an ortho-amino anilide functionality, and three chiral centers, as a selective class I histone deacetylase (HDAC) inhibitor (HDAC1 > 2 > 3). Further investigation demonstrated that selective HDAC1/HDAC2 inhibition using compounds or RNA interference induced differentiation and decreased viability in neuroblastoma cell lines. Combined treatment with 13-cis retinoic acid augmented these effects and enhanced activation of retinoic acid signaling. Therefore, by applying a chemical genomic screening approach, we identified selective HDAC1/HDAC2 inhibition as a strategy to induce neuroblastoma differentiation.
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