Class I histone deacetylases (HDACs) are key regulators of cell proliferation and they are frequently dysregulated in cancer cells. We report here the synthesis of a novel series of class-I selective HDAC inhibitors (HDACi) containing a 2-aminobenzamide moiety as a zinc-binding group connected with a central (piperazin-1-yl)pyrazine or (piperazin-1-yl)pyrimidine moiety. Some of the compounds were additionally substituted with an aromatic capping group. Compounds were tested in vitro against human HDAC1, 2, 3, and 8 enzymes and compared to reference class I HDACi (Entinostat (MS-275), Mocetinostat, CI994 and RGFP-966). The most promising compounds were found to be highly selective against HDAC1, 2 and 3 over the remaining HDAC subtypes from other classes. Molecular docking studies and MD simulations were performed to rationalize the in vitro data and to deduce a complete structure activity relationship (SAR) analysis of this novel series of class-I HDACi. The most potent compounds, including 19f, which blocks HDAC1, HDAC2, and HDAC3, as well as the selective HDAC1/HDAC2 inhibitors 21a and 29b, were selected for further cellular testing against human acute myeloid leukemia (AML) and erythroleukemic cancer (HEL) cells, taking into consideration their low toxicity against human embryonic HEK293 cells. We found that 19f is superior to the clinically tested class-I HDACi Entinostat (MS-275). Thus, 19f is a new and specific HDACi with the potential to eliminate blood cancer cells of various origins.
- MeSH
- antitumorózní látky chemická syntéza chemie farmakokinetika farmakologie MeSH
- benzamidy chemická syntéza chemie farmakologie MeSH
- HEK293 buňky MeSH
- inhibitory histondeacetylas chemická syntéza chemie farmakokinetika farmakologie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- ortoaminobenzoáty chemická syntéza chemie MeSH
- protonová magnetická rezonanční spektroskopie MeSH
- pyraziny chemie MeSH
- pyridiny chemická syntéza chemie farmakologie MeSH
- simulace molekulového dockingu * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
This open-label, single-arm phase II study examined efficacy, safety, pharmacokinetics, and biomarkers of histone deacetylase (HDAC) inhibitor resminostat in patients with relapsed or refractory Hodgkin lymphoma. Thirty-seven heavily pretreated patients received 600 (19 patients) or 800 mg (18 patients) oral resminostat daily for the initial 5 days of 14-day treatment cycles. Objective response rate (ORR) (primary) was 34% reaching disease control in 54% patients. Most patients (69%) showed reduced tumor size and reduced [18F]-FDG uptake in target lesions (71%). Median progression-free survival (PFS) was 2.3 months (95%CI [1.3; 3.3]) and median overall survival (OS) was 12.5 months (95%CI [9.6; 18.6]). Patients who responded or stabilized under resminostat had a 10-month longer OS than patients who progressed. Efficacy assessment, pharmacodynamics, and exploratory biomarker results followed plasma levels, showed target engagement and epigenetic modulations. Common drug-related adverse events (AEs) were nausea, vomiting, anemia, thrombocytopenia, and fatigue, mainly grade 1 or 2.
- MeSH
- antitumorózní látky aplikace a dávkování škodlivé účinky farmakokinetika terapeutické užití MeSH
- biologické markery MeSH
- chemorezistence MeSH
- dospělí MeSH
- Hodgkinova nemoc diagnóza farmakoterapie etiologie mortalita MeSH
- inhibitory histondeacetylas aplikace a dávkování škodlivé účinky farmakokinetika terapeutické užití MeSH
- Kaplanův-Meierův odhad MeSH
- kyseliny hydroxamové aplikace a dávkování škodlivé účinky farmakokinetika terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- opakovaná terapie MeSH
- PET/CT MeSH
- pozitronová emisní tomografie MeSH
- recidiva MeSH
- senioři MeSH
- sulfonamidy aplikace a dávkování škodlivé účinky farmakokinetika terapeutické užití MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze II MeSH
