Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 19, Pages 14620-14646Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c01119
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Funding
- DSO-Netzwerkverbundes, HHU Dusseldorf
- KinderKrebsForschung e.V.
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [270650915, GRK 2158, CRC992]
- Deutsches Konsortium fur Translationale Krebsforschung (DKTK), Joint funding (Targeting MYC L*10)
- TransOnc priority program of the German Cancer Aid [70112951]
- Lowenstern e. V.
- Katharina-Hardt Foundation
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Novel multitarget drugs showed stronger anti-leukemia activity by inducing apoptosis more effectively than combination therapies, suggesting an advantage of dual HDAC/BET inhibitors over two single targeted compounds.
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.
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