19008-43-6Relevant articles and documents
Class I/IIb-Selective HDAC Inhibitor Exhibits Oral Bioavailability and Therapeutic Efficacy in Acute Myeloid Leukemia
Bukhari, Shazreh,Cabral, Aaron D.,De Araujo, Elvin D.,Gawel, Justyna M.,Gunning, Patrick T.,He, Liying,Johns, Alexandra E.,Manaswiyoungkul, Pimyupa,Nawar, Nabanita,Olaoye, Olasunkanmi O.,Raouf, Yasir S.,Sedighi, Abootaleb,Shouksmith, Andrew E.,Sina, Diana
supporting information, p. 56 - 64 (2020/01/31)
The HDAC inhibitor 4-tert-butyl-N-(4-(hydroxycarbamoyl)phenyl)benzamide (AES-350, 51) was identified as a promising preclinical candidate for the treatment of acute myeloid leukemia (AML), an aggressive malignancy with a meagre 24% 5-year survival rate. Through screening of low-molecular-weight analogues derived from the previously discovered novel HDAC inhibitor, AES-135, compound 51 demonstrated greater HDAC isoform selectivity, higher cytotoxicity in MV4-11 cells, an improved therapeutic window, and more efficient absorption through cellular and lipid membranes. Compound 51 also demonstrated improved oral bioavailability compared to SAHA in mouse models. A broad spectrum of experiments, including FACS, ELISA, and Western blotting, were performed to support our hypothesis that 51 dose-dependently triggers apoptosis in AML cells through HDAC inhibition.
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 L.,Gunning, Patrick T.
supporting information, p. 2651 - 2665 (2019/03/17)
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.
Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase
Brough, Paul A.,Baker, Lisa,Bedford, Simon,Brown, Kirsten,Chavda, Seema,Chell, Victoria,D’Alessandro, Jalanie,Davies, Nicholas G. M.,Davis, Ben,Le Strat, Loic,Macias, Alba T.,Maddox, Daniel,Mahon, Patrick C.,Massey, Andrew J.,Matassova, Natalia,McKenna, Sean,Meissner, Johannes W. G.,Moore, Jonathan D.,Murray, James B.,Northfield, Christopher J.,Parry, Charles,Parsons, Rachel,Roughley, Stephen D.,Shaw, Terry,Simmonite, Heather,Stokes, Stephen,Surgenor, Allan,Stefaniak, Emma,Robertson, Alan,Wang, Yikang,Webb, Paul,Whitehead, Neil,Wood, Mike
supporting information, p. 2271 - 2286 (2017/04/03)
Libraries of nonpurified resorcinol amide derivatives were screened by surface plasmon resonance (SPR) to determine the binding dissociation constant (off-rate, kd) for compounds binding to the pyruvate dehydrogenase kinase (PDHK) enzyme. Parallel off-rate measurements against HSP90 and application of structure-based drug design enabled rapid hit to lead progression in a program to identify pan-isoform ATP-competitive inhibitors of PDHK. Lead optimization identified selective sub-100-nM inhibitors of the enzyme which significantly reduced phosphorylation of the E1α subunit in the PC3 cancer cell line in vitro.
