Deciphering the Therapeutic Potential of Novel Pentyloxyamide-Based Class I, IIb HDAC Inhibitors against Therapy-Resistant Leukemia

Deciphering the Therapeutic Potential of Novel Pentyloxyamide-Based Class I, IIb HDAC Inhibitors against Therapy-Resistant Leukemia

Histone deacetylase inhibitors (HDACi) are established anticancer drugs, especially in hematological cancers. This study aimed to design, synthesize, and evaluate a set of HDACi featuring a pentyloxyamide connecting unit linker region and substituted phenylthiazole cap groups. A structural optimizat...

Full description

Saved in:
Bibliographic Details
Main Author: Fabian Fischer (1519975) (author)
Other Authors: Julian Schliehe-Diecks (9328092) (author), Jia-Wey Tu (20347459) (author), Tanja Gangnus (18453288) (author), Yu Lin Ho (20347462) (author), Mara Hebeis (20347465) (author), Leandro A. Alves Avelar (11918921) (author), Katerina Scharov (20347468) (author), Titus Watrin (20347471) (author), Marie Kemkes (20347474) (author), Pawel Stachura (20347477) (author), Katharina Daugs (20347480) (author), Lukas Biermann (19786133) (author), Josefa Kremeyer (20347483) (author), Nadine Horstick (20347486) (author), Ingrid Span (1321215) (author), Aleksandra A. Pandyra (8444013) (author), Arndt Borkhardt (2891) (author), Holger Gohlke (525601) (author), Matthias U. Kassack (534448) (author), Bjoern B. Burckhardt (6930629) (author), Sanil Bhatia (5945495) (author), Thomas Kurz (1648405) (author)
Published: 2024
Subjects:
Biochemistry
Molecular Biology
Pharmacology
Cancer
Hematology
Biological Sciences not elsewhere classified
Chemical Sciences not elsewhere classified
nanomolar inhibitory activity
intermediate microsomal stability
excellent plasma stability
established anticancer drugs
displayed synergistic activity
catalytic domain 2
iib hdac inhibitors
histone deacetylase class
4m </ b
4d </ b
several approved hdaci
iib enzymes
based class
therapeutic potential
study aimed
ray crystallography
promising profile
novel pentyloxyamide
hematological cancers
hdaci featuring
effectively inhibited
demonstrated comparable
danio rerio
binding modes
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Histone deacetylase inhibitors (HDACi) are established anticancer drugs, especially in hematological cancers. This study aimed to design, synthesize, and evaluate a set of HDACi featuring a pentyloxyamide connecting unit linker region and substituted phenylthiazole cap groups. A structural optimization program yielded HDACi with nanomolar inhibitory activity against histone deacetylase class I/IIb enzymes. The novel inhibitors (<b>4d</b> and <b>4m</b>) showed superior antileukemic activity compared to several approved HDACi. Furthermore, <b>4d</b> and <b>4m</b> displayed synergistic activity when combined with chemotherapeutics, decitabine, and clofarabine. In vitro pharmacokinetic studies showed the most promising profile for <b>4d</b> with intermediate microsomal stability, excellent plasma stability, and concentration-independent plasma protein binding. Additionally, <b>4d</b> demonstrated comparable in vivo pharmacokinetics to vorinostat. When administered in vivo, <b>4d</b> effectively inhibited the proliferation of leukemia cells without causing toxicity. Furthermore, the binding modes of <b>4d</b> and <b>4m</b> to the catalytic domain 2 of HDAC6 from Danio rerio were determined by X-ray crystallography.

Similar Items