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

Fischer F, Schliehe-Diecks J, Tu JW, Gangnus T, Ho YL, Hebeis M, Alves Avelar LA, Scharov K, Watrin T, Kemkes M, Stachura P, Daugs K, Biermann L, Kremeyer J, Horstick N, Span I, Pandyra AA, Borkhardt A, Gohlke H, Kassack MU, Burckhardt BB, Bhatia S, Kurz T

Publication Type: Journal article

Journal

Journal of Medicinal Chemistry American Chemical Society

DOI: 10.1021/acs.jmedchem.4c02024

Abstract

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 (4d and 4m) showed superior antileukemic activity compared to several approved HDACi. Furthermore, 4d and 4m displayed synergistic activity when combined with chemotherapeutics, decitabine, and clofarabine. In vitro pharmacokinetic studies showed the most promising profile for 4d with intermediate microsomal stability, excellent plasma stability, and concentration-independent plasma protein binding. Additionally, 4d demonstrated comparable in vivo pharmacokinetics to vorinostat. When administered in vivo, 4d effectively inhibited the proliferation of leukemia cells without causing toxicity. Furthermore, the binding modes of 4d and 4m to the catalytic domain 2 of HDAC6 from Danio rerio were determined by X-ray crystallography.

Authors with CRIS profile

Mara Hebeis Professur für Bioanorganische Chemie Ingrid Span Professur für Bioanorganische Chemie

Involved external institutions

Heinrich-Heine-Universität Düsseldorf DE Germany (DE) Westfälische Wilhelms-Universität (WWU) Münster DE Germany (DE)

How to cite

APA:

Fischer, F., Schliehe-Diecks, J., Tu, J.W., Gangnus, T., Ho, Y.L., Hebeis, M.,... Kurz, T. (2024). Deciphering the Therapeutic Potential of Novel Pentyloxyamide-Based Class I, IIb HDAC Inhibitors against Therapy-Resistant Leukemia. Journal of Medicinal Chemistry. https://doi.org/10.1021/acs.jmedchem.4c02024

MLA:

Fischer, Fabian, et al. "Deciphering the Therapeutic Potential of Novel Pentyloxyamide-Based Class I, IIb HDAC Inhibitors against Therapy-Resistant Leukemia." Journal of Medicinal Chemistry (2024).

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