|Publication Type||Journal Article|
|Year of Publication||2013|
|Authors||Frumm, 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|
|Journal||Chemistry & biology|
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.