A Novel Selective HDAC11 Inhibitor with Broad Anti-Cancer Efficacy

HDAC11 is a Histone Deacetylase (HDAC) enzyme. However, HDAC11 has a high defatty-acylase activity while its deacetylation activity is virtually nonexistent, which is linked to poor prognosis in multiple cancers. This suggests that inhibition of HDAC11 can be used to treat cancers by modulating protein function. No potent and selective inhibitors for the defatty-acylase activity of HDAC11 exist, as previously available HDAC11-selective inhibitors show limited or no ability to prevent this activity in cell cultures.

Researchers at GW developed TD047, a novel selective inhibitor of HDAC11, which has nanomolar potency for HDAC11 defatty-acylase activity in enzymatic assays and is selective relative to other HDACs. Studies done by the researchers showed that TD047 is a tight-binding reversible inhibitor and functions in cell culture at nanomolar potency. In addition, the researchers showed that it is active at low nanomolar concentrations and inhibits defatty-acylation of SHMT2, a known substrate of HDAC11. TD047 also exhibits significant anti-cancer efficacy, particularly in overcoming drug resistance in melanoma and other cancers.

Figure 1: TD047 reduces tumor size. TD047 successfully reduces melanoma tumor size in vivo.

Advantages:

• Highly potent and selective to HDAC11
• Reversible binding ensures effective inhibition without permanent binding to the enzyme
• Broad anti-cancer efficacy, including melanoma, lung, breast, and liver cancers

Applications:

• Treatment of diseases involving inflammation and immunoregulation
• Cancer treatment
• Overcoming drug resistance to existing therapeutics