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

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 Fishel, Patrick T. Gunning

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2651-2665
Number of pages15
JournalJournal of Medicinal Chemistry
Volume62
Issue number5
DOIs
StatePublished - Mar 14 2019
Externally publishedYes

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Hydroxamic Acids
Histone Deacetylase Inhibitors
Pancreatic Neoplasms
Adenocarcinoma
Survival
Histone Deacetylases
Therapeutics
Standard of Care
Coculture Techniques
Combination Drug Therapy
Neoplasms
Survival Rate
Pharmacokinetics
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Identification and Characterization of AES-135, a Hydroxamic Acid-Based HDAC Inhibitor That Prolongs Survival in an Orthotopic Mouse Model of Pancreatic Cancer. / Shouksmith, Andrew E.; Shah, Fenil; Grimard, Michelle L.; Gawel, Justyna M.; Raouf, Yasir S.; Geletu, Mulu; Berger-Becvar, Angelika; De Araujo, Elvin D.; Luchman, H. Artee; Heaton, William L.; Bakhshinyan, David; Adile, Ashley A.; Venugopal, Chitra; O'Hare, Thomas; Deininger, Michael W.; Singh, Sheila K.; Konieczny, Stephen F.; Weiss, Samuel; Fishel, Melissa; Gunning, Patrick T.

In: Journal of Medicinal Chemistry, Vol. 62, No. 5, 14.03.2019, p. 2651-2665.

Research output: Contribution to journalArticle

Shouksmith, AE, Shah, F, Grimard, ML, Gawel, JM, Raouf, YS, Geletu, M, Berger-Becvar, A, De Araujo, ED, Luchman, HA, Heaton, WL, Bakhshinyan, D, Adile, AA, Venugopal, C, O'Hare, T, Deininger, MW, Singh, SK, Konieczny, SF, Weiss, S, Fishel, M & Gunning, PT 2019, 'Identification and Characterization of AES-135, a Hydroxamic Acid-Based HDAC Inhibitor That Prolongs Survival in an Orthotopic Mouse Model of Pancreatic Cancer', Journal of Medicinal Chemistry, vol. 62, no. 5, pp. 2651-2665. https://doi.org/10.1021/acs.jmedchem.8b01957
Shouksmith, Andrew E. ; Shah, Fenil ; Grimard, Michelle L. ; Gawel, Justyna M. ; Raouf, Yasir S. ; Geletu, Mulu ; Berger-Becvar, Angelika ; De Araujo, Elvin D. ; Luchman, H. Artee ; Heaton, William L. ; Bakhshinyan, David ; Adile, Ashley A. ; Venugopal, Chitra ; O'Hare, Thomas ; Deininger, Michael W. ; Singh, Sheila K. ; Konieczny, Stephen F. ; Weiss, Samuel ; Fishel, Melissa ; Gunning, Patrick T. / Identification and Characterization of AES-135, a Hydroxamic Acid-Based HDAC Inhibitor That Prolongs Survival in an Orthotopic Mouse Model of Pancreatic Cancer. In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 5. pp. 2651-2665.
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AU - Gawel, Justyna M.

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AU - Heaton, William L.

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AU - Adile, Ashley A.

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AU - O'Hare, Thomas

AU - Deininger, Michael W.

AU - Singh, Sheila K.

AU - Konieczny, Stephen F.

AU - Weiss, Samuel

AU - Fishel, Melissa

AU - Gunning, Patrick T.

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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.

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