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

Abstract

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.

• Authors: Andrew E Shouksmith, Fenil Shah, Michelle L Grimard, Justyna M Gawel, Yasir S Raouf, Mulu Geletu, Angelika Berger-Becvar, Elvin D de Araujo, H Artee Luchman, William L Heaton, David Bakhshinyan, Ashley A Adile, Chitra Venugopal, Thomas O'Hare, Michael W Deininger, Sheila K Singh, Stephen F Konieczny, Samuel Weiss, Melissa L Fishel, Patrick T Gunning
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 62 Issue 5 Pg. 2651-2665 (03 14 2019) ISSN: 1520-4804 [Electronic] United States
• PMID: 30776234 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• AES-135
• Benzamides
• Histone Deacetylase Inhibitors
• Hydrocarbons, Fluorinated
• Hydroxamic Acids
• Sulfonamides

Topics

• Animals
• Apoptosis (drug effects)
• Benzamides (chemistry, pharmacokinetics, pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Coculture Techniques
• Disease Models, Animal
• Histone Deacetylase Inhibitors (chemistry, pharmacokinetics, pharmacology, therapeutic use)
• Humans
• Hydrocarbons, Fluorinated (chemistry, pharmacokinetics, pharmacology, therapeutic use)
• Hydroxamic Acids (chemistry)
• Mice
• Pancreatic Neoplasms (drug therapy, pathology)
• Sulfonamides (chemistry, pharmacokinetics, pharmacology, therapeutic use)