MYCN-driven neuroblastoma is derived from embryonal precancer cells, which persist postnatally due to the loss of the normal death response which follows trophic factor withdrawal, a widespread regulatory process needed for normal organogenesis (1, 2). We performed high-throughput screening to identify novel compounds that restore the death response in MYCN-expressing precursor B lymphocytes. From an initial library of 40,000 compounds screening, we generated a short-list of 5 compounds displaying cytotoxic activity against MYCN-expressing pre-B cells in the absence of interleukin-7 but had a minimal effect on cells in the presence of trophic factor. Ganglia cells harvested from 2-week old wild-type and homozygous TH-MYCN mice were treated with five compounds and only one compound, PB-798, showed significant reduction in ganglia cell growth in the absence of nerve growth factor, evidently restoring death sensitivity following trophic growth factor withdrawal in these MYCN-driven persistent rest cells. PB-798 treatment also resulted in significant reduction of MYCN protein expression levels in MYCN-overexpressing pre-B cells but not in the pre-B cells transfected with the empty vector. The treatment of transgenic MYCN overexpressing zebrafish with PB-798 resulted in significant inhibition of MYCN-induced neuroblastic hyperplasia in the interrenal gland, and a model of the first step towards neuroblastoma initiation, did not show any toxicity in normal zebrafish embryos as measured by no change in their swim bladder size. We commenced a pilot study in the TH-MYCN mice model to test the safety and efficacy of PB-798. We found increased tumour-free survival and inhibition of tumour initiation from 120 mg/kg/day PB-798 treatment compared to the DMSO treated control in TH-MYCN homozygous mice. Transcriptomic comparisons for cells treated with PB798 repressed cholesterol biosynthesis as a mechanism of action. Taken together, a novel small molecule compound PB-798, can restore the death response to trophic factor withdrawal in MYCN-initiated malignant cells, inhibit the initiation of neuroblastoma in MYCN-drive cancer, with little effects on normal cells in vitro and in vivo.