Screening of small molecule chemical library identifies leads that reduce cholesterol accumulation in human NPC1 fibroblasts

Although considerable progress has been made in finding a therapy for Niemann-Pick type C1 (NPC1) disease, there still is no effective approved treatment. Previously, we reported results from a small molecule screen that was conducted on Chinese Hamster Ovary (CHO) cells (CT60) that lacked NPC1 expression. The hit compounds that were effective in reducing cholesterol accumulation in CT60 cells were not effective on human cells bearing disease-causing mutations in NPC1. Hence, we conducted a new small molecule screen on patient-derived NPC1 skin fibroblasts using a combinatorial library of ~48,000 compounds. We have identified several compounds that corrected the phenotype in human heterozygous mutant NPC1 skin fibroblasts (GM03123) bearing the inactivating I1061T mutation in one allele and another set of inactivating mutations in the other. Among the hit compounds were several histone deacetylase inhibitors, which we have explored further and reported previously. With the determination of the structure of NPC1 protein and the development of computational docking algorithms, it seems worthwhile to show the structures of 128 compounds that reproducibly reduced cholesterol storage in mutant NPC1 fibroblasts but with no known mechanism of action. These compounds were not toxic and specifically effective on mutant cells but not on NPC1-/- cells, indicating on-target effect directly or indirectly.