NDSU Scientists have developed a technology to activate or enhance inhibition of histone deacetylase-8 (HDAC-8). The technology is based on the ability of “activators” (N-acylthioureas) to bind directly to HDAC-8.
When provided alone, N-acylthioureas enhance normal substrate binding and have promise for treatment of Cornelia de Lang syndrome, some neuroblastomas, and other ‘smooth muscle contractility’ diseases.
When provided in combination with an HDAC-8 inhibitor, binding of N-acylthioureas to HDAC-8 strengthens the inhibitor activity. Through this mechanism, N-acylthioureas have promise in combination with HDAC-8 inhibitors in the treatment of leukemia, neuroblastoma, and other diseases treated by HDAC-8 inhibitors.
- Therapeutic treatment of Cornelia de Lang syndrome, and other diseases resulting from the lost or reduced activity of HDAC-8
- Adjuvant to increase the performance of inhibiting therapeutics of multiple illnesses resulting from the excessive activity of HDAC-8
- N-acylthioureas bind directly to HDAC-8, creating a more active enzyme conformation (direct binding means performance is independent of other cellular substrates that may or may not be present, unlike sirtuin activation that requires additional substrate binding)
- Activator binding stabilizes a specific conformational state that re-activates disabled HDAC-8 in cells of Cornelia de Lang patients
- Activator binding in the presence of HDAC-8 inhibitors produces an adjuvant effect, enabling HDAC-8 to preferentially and stably bind selected HDAC-8 inhibitors rather than native HDAC-8 substrates, thereby enhancing the therapeutic performance of those inhibitors
- The adjuvant effect appears to lead to indirect activation of wildtype p53, enhancing tumor-suppressing effects of p53 in cancers where wildtype p53 is present
N-acetylthioureas were shown to bind directly to HDAC-8, and this binding activates the enzyme, resulting in de-acetylation of histones. The binding also induces highly stable conformational states in which binding of inhibitors is more likely than binding of native substrates.
This enables N-acetylthioureas to potentially act as activators of ‘normal’ actions in the absence of HDAC-8 inhibitors, and activators of inhibitor binding when inhibitors are present, enhancing the therapeutic activity of those HDAC-8 inhibitors.