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

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

  • J Med Chem. 2019 Mar 14;62(5):2651-2665. doi: 10.1021/acs.jmedchem.8b01957.
Andrew E Shouksmith 1,  Fenil Shah,  Michelle L Grimard,  Justyna M Gawel 1,  Yasir S Raouf 1,  Mulu Geletu 1,  Angelika Berger-Becvar 1,  Elvin D de Araujo 1,  H Artee Luchman 2,  William L Heaton 3,  David Bakhshinyan 4,  Ashley A Adile 4,  Chitra Venugopal 4,  Thomas O'Hare 3,  Michael W Deininger 3,  Sheila K Singh 4,  Stephen F Konieczny 5,  Samuel Weiss 2,  Melissa L Fishel,  Patrick T Gunning 1
Affiliations

Affiliations

  • 1 Department of Chemical and Physical Sciences , University of Toronto Mississauga , 3359 Mississauga Road , Mississauga , Ontario L5L 1C6 , Canada.
  • 2 Hotchkiss Brain Institute and Department of Cell Biology and Anatomy , University of Calgary , Calgary , Alberta T2N 1N4 , Canada.
  • 3 Huntsman Cancer Institute, Division of Hematology and Hematologic Malignancies , University of Utah , Salt Lake City , Utah 84112 , United States.
  • 4 McMaster Stem Cell and Cancer Research Institute , McMaster University , Hamilton , Ontario L8S 4L8 , Canada.
  • 5 Department of Biological Sciences , Purdue University , West Lafayette , Indiana 47907 , United States.
PMID: 30776234 DOI: 10.1021/acs.jmedchem.8b01957
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-114483
    98.21%, HDAC3/HDAC6/HDAC8/HDAC11 抑制剂
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