Oxa Analogues of Nexturastat A Demonstrate Improved HDAC6 Selectivity and Superior Antileukaemia Activity

Abstract

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.

Establishment and Evaluation of Dual HDAC/BET Inhibitors as Therapeutic Options for Germ Cell Tumors and Other Urological Malignancies

“… 32 ), and class IIb (MPK187 and MPK377; ref. 33 ) inhibitors have been previously described. To evaluate the importance of class I selective inhibitors, two types of class I selective inhibitors were designed and synthesized, RGFP109-based (LAK78, LAK86, LAK88, LAK92, LAK94, LAK96, LAK98, and LAK100) and Entinostat-based inhibitors (LAK102 and LAK104).…”

“…Two types of BRDi were synthesized, +JQ1-based (ASK series) and I-BET 762based (PWK series) inhibitors. The synthesis of the HDAC class I/IIb (KSK64, LAK31, LAK39, LAK41 and YAK61) [29][30][31], pan (MPK409) [32], class I (K79PCHy) [33] and class IIb (MPK187 and MPK377) [34] inhibitors have been previously described. To evaluate the importance of class I selective inhibitors, two types of class I selective inhibitors were designed and synthesized, RGFP109-based (LAK78, LAK86, LAK88, LAK92, LAK94, LAK96, LAK98 and LAK100) and Entinostat-based inhibitors (LAK102 and LAK104).…”

Preferential HDAC6 inhibitors derived from HPOB exhibit synergistic antileukemia activity in combination with decitabine

“…https://doi.org/10.26434/chemrxiv-2024-flvmf ORCID: https://orcid.org/0000-0001-9765-5975 Content not peer-reviewed by ChemRxiv. License: CC BY-NC-ND 4.0 [16][17][18] .…”

Identification of mercaptoacetamide-based HDAC6 inhibitors via a lean inhibitor strategy: screening, synthesis, and biological evaluation

“…Up to now, structural variations have mainly been focussed on the cap group and linker unit, while the majority of published inhibitors bears a hydroxamic acid (HAA) zinc-binding moiety. 33–35,37,42,43 Although hydroxamic acids are indeed powerful metal chelators, they are also suspected of mutagenicity and non-specific metal binding, causing side effects and hampering medicinal applications, especially beyond oncology. 44 Considering the pivotal role of HDAC6 in e.g.…”

“…Up to now, structural variations have mainly been focussed on the cap group and linker unit, while the majority of published inhibitors bears a hydroxamic acid (HAA) zinc-binding moiety. [33][34][35]37,42,43 Although hydroxamic acids are indeed powerful metal chelators, a SynBioC Research Group, Department of Green Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium. E-mail: Matthias.Dhooghe@UGent.be b Translational Nuclear Receptor Research, VIB-UGent Center for Medical they are also suspected of mutagenicity and non-specific metal binding, causing side effects and hampering medicinal applications, especially beyond oncology.…”