PUBLICATION
4-Acyl Pyrrole Capped HDAC Inhibitors: A New Scaffold for Hybrid Inhibitors of BET Proteins and Histone Deacetylases as Antileukemia Drug Leads
- Authors
- Schäker-Hübner, L., Warstat, R., Ahlert, H., Mishra, P., Kraft, F.B., Schliehe-Diecks, J., Schöler, A., Borkhardt, A., Breit, B., Bhatia, S., Hügle, M., Günther, S., Hansen, F.K.
- ID
- ZDB-PUB-210929-32
- Date
- 2021
- Source
- Journal of medicinal chemistry 64(19): 14620-14646 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- 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
- PubMed
- 34582215 Full text @ J. Med. Chem.
Citation
Schäker-Hübner, L., Warstat, R., Ahlert, H., Mishra, P., Kraft, F.B., Schliehe-Diecks, J., Schöler, A., Borkhardt, A., Breit, B., Bhatia, S., Hügle, M., Günther, S., Hansen, F.K. (2021) 4-Acyl Pyrrole Capped HDAC Inhibitors: A New Scaffold for Hybrid Inhibitors of BET Proteins and Histone Deacetylases as Antileukemia Drug Leads. Journal of medicinal chemistry. 64(19):14620-14646.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping