Identification and Characterization of AES-135, a Hydroxamic Acid-Based HDAC Inhibitor That Prolongs Survival in an Orthotopic Mouse Model of Pancreatic Cancer

Pancreatic
ductal adenocarcinoma (PDAC) is an aggressive, incurable cancer with a 20%
1 year survival rate. While standard-of-care therapy can prolong life
in a small fraction of cases, PDAC is inherently resistant to current
treatments, and novel therapies are urgently required. Histone deacetylase
(HDAC) inhibitors are effective in killing pancreatic cancer cells
in in vitro PDAC studies, and although there are a few clinical studies
investigating combination therapy including HDAC inhibitors, no HDAC
drug or combination therapy with an HDAC drug has been approved for
the treatment of PDAC. We developed an inhibitor of HDACs, AES-135, that exhibits nanomolar inhibitory activity against HDAC3, HDAC6,
and HDAC11 in biochemical assays. In a three-dimensional coculture
model, AES-135 kills low-passage patient-derived tumor
spheroids selectively over surrounding cancer-associated fibroblasts
and has excellent pharmacokinetic properties in vivo. In an orthotopic
murine model of pancreatic cancer, AES-135 prolongs survival
significantly, therefore representing a candidate for further preclinical
testing.