TY - JOUR
T1 - Identification and Characterization of AES-135, a Hydroxamic Acid-Based HDAC Inhibitor That Prolongs Survival in an Orthotopic Mouse Model of Pancreatic Cancer
AU - Shouksmith, Andrew E.
AU - Shah, Fenil
AU - Grimard, Michelle L.
AU - Gawel, Justyna M.
AU - Raouf, Yasir S.
AU - Geletu, Mulu
AU - Berger-Becvar, Angelika
AU - De Araujo, Elvin D.
AU - Luchman, H. Artee
AU - Heaton, William L.
AU - Bakhshinyan, David
AU - Adile, Ashley A.
AU - Venugopal, Chitra
AU - O'Hare, Thomas
AU - Deininger, Michael W.
AU - Singh, Sheila K.
AU - Konieczny, Stephen F.
AU - Weiss, Samuel
AU - Fishel, Melissa L.
AU - Gunning, Patrick T.
N1 - Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/3/14
Y1 - 2019/3/14
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.8b01957
DO - 10.1021/acs.jmedchem.8b01957
M3 - Article
C2 - 30776234
AN - SCOPUS:85062769820
SN - 0022-2623
VL - 62
SP - 2651
EP - 2665
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 5
ER -
