acy-1215 and Leukemia--Myeloid--Acute

Using a microwave-assisted protocol, we synthesized 16 peptoid-capped HDAC inhibitors (HDACi) with fluorinated linkers and identified two hit compounds. In biochemical and cellular assays,

Topics: Antineoplastic Agents; Cell Line, Tumor; Decitabine; Histone Deacetylase 1; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Leukemia, Myeloid, Acute; Peptoids

Dysregulated Histone Deacetylase (HDAC) activity across multiple human pathologies have highlighted this family of epigenetic enzymes as critical druggable targets, amenable to small molecule intervention. While efficacious, current approaches using non-selective HDAC inhibitors (HDACi) have been shown to cause a range of undesirable clinical toxicities. To circumvent this, recent efforts have focused on the design of highly selective HDACi as a novel therapeutic strategy. Beyond roles in regulating transcription, the unique HDAC6 (with two catalytic domains) regulates the deacetylation of α-tubulin; promoting growth factor-controlled cell motility, cell division, and metastatic hallmarks. Recent studies have linked aberrant HDAC6 function in various hematological cancers including acute myeloid leukaemia and multiple myeloma. Herein, we report the discovery, in vitro characterization, and biological evaluation of PTG-0861 (JG-265), a novel HDAC6-selective inhibitor with strong isozyme-selectivity (∼36× ) and low nanomolar potency (IC

Topics: Animals; Antineoplastic Agents; Apoptosis; Benzamides; Catalytic Domain; Cell Line, Tumor; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Leukemia, Myeloid, Acute; Male; Mice; Molecular Docking Simulation; Molecular Structure; Protein Binding; Structure-Activity Relationship

Clinically, leukemia patients often suffer from the limited efficacy of chemotherapy and high risks of infection by invasive fungal pathogens. Herein, a novel therapeutic strategy was developed in which a small molecule can simultaneously treat leukemia and invasive fungal infections (IFIs). Novel Janus kinase 2 (JAK2) and histone deacetylase (HDAC) dual inhibitors were identified to possess potent anti-proliferative activity toward hematological cell lines and excellent synergistic effects with fluconazole to treat resistant Candida albicans infections. In particular, compound 20a, a highly active and selective JAK2/HDAC6 dual inhibitor, showed excellent in vivo antitumor efficacy in several acute myeloid leukemia (AML) models and synergized with fluconazole for the treatment of resistant C. albicans infections. This study highlights the therapeutic potential of JAK2/HDAC dual inhibitors in treating AML and IFIs and provides an efficient strategy for multitargeting drug discovery.

Topics: Animals; Apoptosis; Candida albicans; Cell Cycle; Cell Line, Tumor; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Humans; Invasive Fungal Infections; Janus Kinase 2; Leukemia, Myeloid, Acute; Mice