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

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.

Identification of a BAZ2A-Bromodomain Hit Compound by Fragment Growing

“…The acetylpyrrole headgroup has already been explored in BRD4 and CREBBP inhibitors (Figure e,f), also cross-reacting with BRD7, BRD9, and HDACs. − However, compound 104 features a unique thiazole ring as scaffold. Furthermore, its binding mode is different, as its ethyl-isoxazole tail folds back in the bromodomain Kac pocket and stacks with the thiazole ring.…”

Development and Biological Evaluation of the First Highly Potent and Specific Benzamide-Based Radiotracer [18F]BA3 for Imaging of Histone Deacetylases 1 and 2 in Brain

“…In vitro inhibitory activities against HDAC1−3 and HDAC6 were measured as previously published [ 68 ] with minor modifications. In short, 3-fold serial dilutions of test compounds and controls in assay buffer (50 mM Tris-HCl, pH = 8.0, 137 mM NaCl, 2.7 mM KCl, 1.0 mM MgCl 2 × 6 H 2 O, 0.1 mg/mL BSA) were prepared, and 5.0 µL were transferred into black microplates (OptiPlate-96, PerkinElmer Inc., Waltham, MA, USA).…”

Virtual Special Issue: Epigenetics 2022

“…There is also a Perspective discussing the potential for using selective HDAC6 inhibitors as a treatment for aspects of cystic fibrosis-associated lung disease . The development of dual inhibitors of the BET bromodomains and the HDAC enzymes as drug leads to treat leukemia is also described …”

“…64 The development of dual inhibitors of the BET bromodomains and the HDAC enzymes as drug leads to treat leukemia is also described. 65 Methyltransferase enzymes are also an area of significant activity in epigenetic medicinal chemistry. This is exemplified This compound is being investigated as a way of inhibiting this new synthetically lethal drug target for the treatment of MTAPdeleted cancers.…”