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Oxa Analogues of Nexturastat A Demonstrate Improved HDAC6 Selectivity and Superior Antileukaemia Activity
Author(s) -
Pflieger Marc,
Sönnichsen Melf,
HorstickMuche Nadine,
Yang Jing,
SchlieheDiecks Julian,
Schöler Andrea,
Borkhardt Arndt,
Hamacher Alexandra,
Kassack Matthias U.,
Hansen Finn K.,
Bhatia Sanil,
Kurz Thomas
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202001011
Subject(s) - hdac6 , histone deacetylase , hydroxamic acid , chemistry , hdac1 , pharmacology , cancer research , biochemistry , medicine , histone , gene , stereochemistry
The acetylome is important for maintaining the homeostasis of cells. Abnormal changes can result in the pathogenesis of immunological or neurological diseases, and degeneration can promote the manifestation of cancer. In particular, pharmacological intervention in the acetylome with pan‐histone deacetylase (HDAC) inhibitors is clinically validated. However, these drugs exhibit an undesirable risk‐benefit profile due to severe side effects. Selective HDAC inhibitors might promote patient compliance and represent a valuable opportunity in personalised medicine. Therefore, we envisioned the development of HDAC6‐selective inhibitors. During our lead structure identification, we demonstrated that an alkoxyurea‐based connecting unit proves to be beneficial for HDAC6 selectivity and established the synthesis of alkoxyurea‐based hydroxamic acids. Herein, we report highly potent N ‐alkoxyurea‐based hydroxamic acids with improved HDAC6 preference compared to nexturastat A. We further validated the biological activity of these oxa analogues of nexturastat A in a broad subset of leukaemia cell lines and demonstrated their superior anti‐proliferative properties compared to nexturastat A.