2. Academic Validation
  3. Development of Fluorinated Peptoid-Based Histone Deacetylase (HDAC) Inhibitors for Therapy-Resistant Acute Leukemia

Development of Fluorinated Peptoid-Based Histone Deacetylase (HDAC) Inhibitors for Therapy-Resistant Acute Leukemia

  • J Med Chem. 2022 Nov 24;65(22):15457-15472. doi: 10.1021/acs.jmedchem.2c01418.
Nina Reßing 1 2,  Julian Schliehe-Diecks 3,  Paris R Watson 4,  Melf Sönnichsen 3,  Abigail D Cragin 4,  Andrea Schöler 2,  Jing Yang 3 5,  Linda Schäker-Hübner 1,  Arndt Borkhardt 3,  David W Christianson 4,  Sanil Bhatia 3,  Finn K Hansen 1
Affiliations

Affiliations

  • 1 Pharmaceutical Institute, Pharmaceutical and Cell Biological Chemistry, University of Bonn, An der Immenburg 4, 53121Bonn, Germany.
  • 2 Institute for Drug Discovery, Medical Faculty, Leipzig University, Brüderstraße 34, 04103Leipzig, Germany.
  • 3 Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University Düsseldorf, Moorenstrasse 5, 40225Düsseldorf, Germany.
  • 4 Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania19104-6323, United States.
  • 5 Department of Medicine, Yangzhou Polytechnic College, West Wenchang Road 458, Yangzhou225009, P. R. China.
PMID: 36351184 DOI: 10.1021/acs.jmedchem.2c01418
Abstract

Using a microwave-assisted protocol, we synthesized 16 peptoid-capped HDAC inhibitors (HDACi) with fluorinated linkers and identified two hit compounds. In biochemical and cellular assays, 10h stood out as a potent unselective HDACi with remarkable cytotoxic potential against different therapy-resistant leukemia cell lines. 10h demonstrated prominent antileukemic activity with low cytotoxic activity toward healthy cells. Moreover, 10h exhibited synergistic interactions with the DNA Methyltransferase Inhibitor decitabine in AML cell lines. The comparison of crystal structures of HDAC6 complexes with 10h and its nonfluorinated counterpart revealed a similar occupation of the L1 loop pocket but slight differences in zinc coordination. The substitution pattern of the acyl residue turned out to be crucial in terms of isoform selectivity. The introduction of an isopropyl group onto the phenyl ring provided the highly HDAC6-selective inhibitor 10p, which demonstrated moderate synergy with decitabine and exceeded the HDAC6 selectivity of tubastatin A.

Figures
Products