2. Academic Validation
  3. Preferential HDAC6 inhibitors derived from HPOB exhibit synergistic antileukemia activity in combination with decitabine

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

  • Eur J Med Chem. 2024 Jun 5:272:116447. doi: 10.1016/j.ejmech.2024.116447.
Maik Tretbar 1,  Julian Schliehe-Diecks 2,  Lukas von Bredow 1,  Kathrin Tan 3,  Martin Roatsch 1,  Jia-Wey Tu 2,  Marie Kemkes 2,  Melf Sönnichsen 2,  Andrea Schöler 1,  Arndt Borkhardt 2,  Sanil Bhatia 4,  Finn K Hansen 5
Affiliations

Affiliations

  • 1 Institute for Drug Discovery, Medical Faculty, Leipzig University, Brüderstraße 34, 04103, Leipzig, Germany.
  • 2 Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany.
  • 3 Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.
  • 4 Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany. Electronic address: sanil.bhatia@med.uni-duesseldorf.de.
  • 5 Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany. Electronic address: finn.hansen@uni-bonn.de.
PMID: 38714044 DOI: 10.1016/j.ejmech.2024.116447
Abstract

Histone deacetylase 6 (HDAC6) is an emerging drug target to treat oncological and non-oncological conditions. Since highly selective HDAC6 inhibitors display limited Anticancer activity when used as single agent, they usually require combination therapies with Other chemotherapeutics. In this work, we synthesized a mini library of analogues of the preferential HDAC6 Inhibitor HPOB in only two steps via an Ugi four-component reaction as the key step. Biochemical HDAC inhibition and cell viability assays led to the identification of 1g (highest antileukemic activity) and 2b (highest HDAC6 inhibition) as hit compounds. In subsequent combination screens, both 1g and especially 2b showed synergy with DNA Methyltransferase Inhibitor decitabine in acute myeloid leukemia (AML). Our findings highlight the potential of combining HDAC6 inhibitors with DNA Methyltransferase inhibitors as a strategy to improve AML treatment outcomes.

Keywords

Cancer; Epigenetics; HDAC inhibitors; Histone deacetylases; Leukemia.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-161516
    HDAC6抑制剂
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z