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Novel HDAC6-Selective Inhibitor for Glioblastoma Treatment

Glioblastoma multiforme is one of the deadliest types of cancer. Various approaches are being investigated and inhibition of histone deacetylases (HDACs) is showing promising results. However, since non-selective HDAC inhibition can cause serious side effects, scientists are focusing on the development of selective inhibitors. HDAC6 is a unique HDAC with a wider binding side expressed primarily in the cytoplasm. Since its targets are non- histone proteins, it has a role in cytoskeletal organisation and chaperone activities. We have developed a novel HDAC6 selective inhibitor – sahaquine. Sahaquine is a primaquine derivative linked with a hydroxamic acid moiety via a glutaric acid linker. The quinoline ring of primaquine is the capping group that fits better into the wider active site of HDAC6. Sahaquine inhibited HDAC6 in nanomolar concentrations without affecting other HDACs in glioblastoma cells. Additionally, sahaquine inhibited glioblastoma cell invasion and decreased levels of EGFR and its downstream targets – phosphorylated AKT and phosphorylated ERK1/2. To investigate sahaquine's safety and metabolism, a matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI MSI) method applied to zebrafish larvae was developed.

glioblastoma ; HDAC6 ; primaquine ; hydroxamic acid

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