4‑Acyl Pyrrole Capped HDAC Inhibitors: A New Scaffold for Hybrid Inhibitors of BET Proteins and Histone Deacetylases as Antileukemia Drug Leads

Multitarget drugs are an emerging alternative to combination therapies. In three iterative cycles of design, synthesis, and biological evaluation, we developed a novel type of potent hybrid inhibitors of bromodomain, and extra-terminal (BET) proteins and histone deacetylases (HDACs) based on the BET...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2021-10, Vol.64 (19), p.14620-14646
Main Authors: Schäker-Hübner, Linda, Warstat, Robin, Ahlert, Heinz, Mishra, Pankaj, Kraft, Fabian B, Schliehe-Diecks, Julian, Schöler, Andrea, Borkhardt, Arndt, Breit, Bernhard, Bhatia, Sanil, Hügle, Martin, Günther, Stefan, Hansen, Finn K
Format: Article
Language:English
Subjects:
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Apoptosis - drug effects
Cell Cycle Proteins - antagonists & inhibitors
Cell Line, Tumor
Drug Screening Assays, Antitumor
Histone Deacetylases - chemistry
Histone Deacetylases - pharmacology
Histone Deacetylases - therapeutic use
Humans
Leukemia - drug therapy
Leukemia - pathology
Nuclear Proteins - antagonists & inhibitors
Pyrroles - chemistry
Transcription Factors - antagonists & inhibitors
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Summary:Multitarget drugs are an emerging alternative to combination therapies. In three iterative cycles of design, synthesis, and biological evaluation, we developed a novel type of potent hybrid inhibitors of bromodomain, and extra-terminal (BET) proteins and histone deacetylases (HDACs) based on the BET inhibitor XD14 and well-established HDAC inhibitors. The most promising new hybrids, 49 and 61, displayed submicromolar inhibitory activity against HDAC1–3 and 6, and BRD4(1), and possess potent antileukemia activity. 49 induced apoptosis more effectively than the combination of ricolinostat and birabresib (1:1). The most balanced dual inhibitor, 61, induced significantly more apoptosis than the related control compounds 62 (no BRD4(1) affinity) and 63 (no HDAC inhibition) as well as the 1:1 combination of both. Additionally, 61 was well tolerated in an in vivo zebrafish toxicity model. Overall, our data suggest an advantage of dual HDAC/BET inhibitors over the combination of two single targeted compounds.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.1c01119