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Chemistry & biology DOI:10.1016/j.chembiol.2013.03.020

Selective HDAC1/HDAC2 Inhibitors Induce Neuroblastoma Differentiation.

Publication TypeJournal Article
Year of Publication2013
AuthorsFrumm, SM, Fan, ZP, Ross, KN, Duvall, JR, Gupta, S, VerPlank, L, Suh, BC, Holson, E, Wagner, FF, Smith, WB, Paranal, RM, Bassil, CF, Qi, J, Roti, G, Kung, AL, Bradner, JE, Tolliday, N, Stegmaier, K
JournalChemistry & biology
Date Published2013/05/23

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.