Identification of Novel Small-Molecule Kinase Modulators for the Treatment of Neuroblastoma

• Main Authors: André Serra-Roma, Olga Shakhova
• Format: Article
• Language: English
• Published: Adis, Springer Healthcare 2020-04-01
• Series: Oncology and Therapy
• Subjects: Drug discovery; High throughput screening; Kinase inhibitors; Neuroblastoma
• Online Access: https://doi.org/10.1007/s40487-020-00113-5

Abstract Neuroblastoma represents 8–10% of all childhood cancer cases and is responsible for 15% of all cancer-related deaths in infants. Even though patients with low- and intermediate-risk disease have a good prognosis, the 5-year survival rate of the vast majority of patients with high-risk neuroblastoma is 50%. Despite extensive research efforts to find a cure for neuroblastoma, current treatment options are still limited. The aim of our study was to identify novel therapeutic compounds using high-throughput drug screening of a small molecule kinase inhibitor library containing 960 compounds. This screening resulted in the identification of two compounds, ST013381 and ST022328, that showed pronounced cytotoxic effects in six human neuroblastoma cell lines in vitro while having reduced effects in the BJ-5ta control cell line. These effects were observed in both MYCN-amplified and -non-amplified cells, indicating that these compounds can affect a wide range of neuroblastomas. Our experiments also revealed that several signaling pathways underlie the selective elimination of neuroblastoma cells by the ST013381 and ST022328 compounds. In summary, we have identified two novel compounds with a strong cytotoxic effect in vitro as promising agents for the treatment of neuroblastoma.