Current HDAC Inhibitors in Clinical Trials

Epigenetic modifications in eukaryotic biological pathways can lead to the up- or downregulation of regulatory proteins contributing to disease onset and progression. In the last three decades, histone deacetylases (HDACs) are among the most studied epigenetic targets. In fact, aberrant HDAC expression is associated with numerous types of cancer and neurodegenerative disorders, making HDACs promising molecular targets for the design of new drugs. Many HDAC inhibitors (HDACi) are currently in clinical evaluation for various types of cancer, and some of them reached the market after approval by the Food and Drug Administration (FDA). The present review summarizes the various HDAC classes and relative isoforms. Then we discuss different class or isoform-selective HDACi with a strong emphasis on late-stage preclinical candidates and drugs in clinical studies. Last but not least, we shed light on the pharmacokinetic challenges and future directions in HDACi design

LSD1 inhibitors for cancer treatment: Focus on multi-target agents and compounds in clinical trials

Histone lysine-specific demethylase 1 (LSD1/KDM1A) was first identified in 2004 as an epigenetic enzyme able to demethylate specific lysine residues of histone H3, namely H3K4me1/2 and H3K9me1/2, using FAD as the cofactor. It is ubiquitously overexpressed in many types of cancers (breast, gastric, prostate, hepatocellular, and esophageal cancer, acute myeloid leukemia, and others) leading to block of differentiation and increase of proliferation, migration and invasiveness at cellular level. LSD1 inhibitors can be grouped in covalent and non-covalent agents. Each group includes some hybrid compounds, able to inhibit LSD1 in addition to other target(s) at the same time (dual or multitargeting compounds). To date, 9 LSD1 inhibitors have entered clinical trials, for hematological and/or solid cancers. Seven of them (tranylcypromine, iadademstat (ORY-1001), bomedemstat (IMG-7289), GSK-2879552, INCB059872, JBI-802, and Phenelzine) covalently bind the FAD cofactor, and two are non-covalent LSD1 inhibitors [pulrodemstat (CC90011) and seclidemstat (SP-2577)]. Another TCP-based LSD1/MAO-B dual inhibitor, vafidemstat (ORY-2001), is in clinical trial for Alzheimer’s diseases and personality disorders. The present review summarizes the structure and functions of LSD1, its pathological implications in cancer and non-cancer diseases, and the identification of LSD1 covalent and non-covalent inhibitors with different chemical scaffolds, including those involved in clinical trials, highlighting their potential as potent and selective anticancer agents

Heterocycle-containing tranylcypromine derivatives endowed with high anti-LSD1 activity

As regioisomers/bioisosteres of 1a, a 4-phenylbenzamide tranylcypromine (TCP) derivative previously disclosed by us, we report here the synthesis and biological evaluation of some (hetero)arylbenzoylamino TCP derivatives 1b-6, in which the 4-phenyl moiety of 1a was shifted at the benzamide C3 position or replaced by 2- or 3-furyl, 2- or 3-thienyl, or 4-pyridyl group, all at the benzamide C4 or C3 position. In anti-LSD1-CoREST assay, all the meta derivatives were more effective than the para analogues, with the meta thienyl analogs 4b and 5b being the most potent (IC50 values ¼ 0.015 and 0.005 lM) and the most selective over MAO-B (selectivity indexes: 24.4 and 164). When tested in U937 AML and prostate cancer LNCaP cells, selected compounds 1a,b, 2b, 3b, 4b, and 5a,b displayed cell growth arrest mainly in LNCaP cells. Western blot analyses showed increased levels of H3K4me2 and/or H3K9me2 confirming the involvement of LSD1 inhibition in these assays

MR Imaging-guided Focused Ultrasound for Treatment of Bone Metastasis

Magnetic resonance (MR) imaging-guided focused ultrasound is an alternative noninvasive method for reducing the pain in skeletal metastases. MR imaging-guided focused ultrasound ablation offers several key advantages over other noninvasive treatment modalities. This technology enables the performance of three-dimensional treatment planning with MR imaging and continuous temperature mapping of treated tissue by using MR thermometry, thereby enabling real-time monitoring of thermal damage in the target zone. The concentration of acoustic energy on the intact surface of cortical bone produces a rapid temperature increase that mediates critical thermal damage to the adjacent periosteum, the most innervated component of mature bone tissue. Such thermal ablation has been shown to be an extremely effective approach for pain management. Energy delivered during MR imaging-guided focused ultrasound ablation and accumulated inside the pathologic soft tissue of the metastases can create a variable amount of tissue necrosis. This technique has also a potential role in achieving local tumor control, allowing remineralization of trabecular bone or reduction in lesion size. The current report presents a detailed step-by-step guide for performing MR imaging- guided focused ultrasound ablation of bone metastases, including use of MR thermometry for monitoring treatment, protocol selection for simple palliation of pain or for local tumor control, and a description of imaging features of periosteal neurolysis or metastasis ablation. Two case studies are also presented: in the first, the technique provided palliation of pain in bone metastases, and in the second, the technique achieved tumor control as further proof of primary efficacy. MR imaging- guided focused ultrasound ablation is a promising method for successful palliation of bone metastasis pain and tumor control, because of the bony structure remodeling induced by thermo-related coagulative necrosis. (c) RSNA, 2013 center dot radiographics.rsna.or

Magnetic resonance-guided focused ultrasound for the treatment of painful bone metastases: role of apparent diffusion coefficient (ADC) and dynamic contrast enhanced (DCE) MRI in the assessment of clinical outcome

Purpose: To assess the correlation between functional MRI, including ADC values obtained from DWI and DCE, and clinical outcome in patients with bone metastases treated with MRgFUS. Methods and materials: Twenty-three patients with symptomatic bone metastases underwent MRgFUS treatment (ExAblate 2100 system InSightec) for pain palliation. All patients underwent clinical and imaging follow-up examinations at 1, 3 and 6 months after treatment. Visual Analog Scale (VAS) score was used to evaluate treatment efficacy in terms of pain palliation while ADC maps obtained by DWI sequences, and DCE data were used for quantitative assessment of treatment response at imaging. Spearman Correlation Coefficient Test was calculated to assess the correlation between VAS, ADC and DCE data. Results: All treatments were performed successfully without adverse events. On the basis of VAS score, 16 (69.6 %) patients were classified as complete clinical responders, 6 (26.1 %) as partial responders and only one (4.3 %) was classified as a non-responder. The mean VAS score decreased from 7.09 ± 1.8 at baseline to 2.65 ± 1.36 at 1 month, 1.04 ± 1.91 at 3 months and 1.09 ± 1.99 at 6 months (p 0.01). Conclusion: In patients with painful bone metastases treated with MRgFUS, ADC and Ktrans variation observed in the ablated lesions correlate with VAS values and may play a role as objective imaging marker of treatment response

Persistence of the sciatic artery: a case report of a combined (complete and incomplete) type causing leg ischemia.

Persistent sciatic artery is a very uncommon embryologic vascular variant, with a prevalence of 0.05% based on angiographic studies. Two different types of this anomaly can occur, complete or incomplete, on the basis of the relationship between sciatic artery and femoral artery. Although many of these patients are asymptomatic, it may represent a threat to the viability of the lower extremity because of atherosclerotic degeneration resulting in aneurysmal dilatation, occlusive thrombosis, or embolic phenomena with distal complication. We present a case of a 64-year-old man with combined, complete and incomplete, type of persistent sciatic artery causing ischemic ulcer of the first toe

Chemically Diverse S. mansoni HDAC8 Inhibitors Reduced Viability in Worm Larval and Adult Stages

Schistosoma mansoni HDAC8 is a reliable target to fight schistosomiasis, and several inhibitors have been reported in the literature up to now. Nevertheless, only a few displayed selectivity over the human deacetylases and some exhibited very low or no activity against parasite larvae and/or adult worms. We report here the in vitro enzyme and biological activity of a small library of HDAC inhibitors from our lab, in many cases exhibiting submicromolar/nanomolar potency against smHDAC8 and diverse degrees of selectivity over hHDAC1 and/or hHDAC6. Such compounds were tested against schistosomula, and a selection of them against the adult forms of S. mansoni, to detect their effect on viability. Some of them showed the highest viability reduction for the larval stage with IC50 values around 1 µM and/or displayed ~ 40-50% activity in adult worms at 10 µM, joined to moderate to no toxicity in human fibroblast MRC-5 cells

Targeting ROS production through inhibition of NADPH oxidases

: NADPH oxidases (NOXs) are transmembrane enzymes that are devoted to the production of reactive oxygen species (ROS). In cancers, dysregulation of NOX enzymes affects ROS production, leading to redox unbalance and tumor progression. Consequently, NOXs are a drug target for cancer therapeutics, although current therapies have off-target effects: there is a need for isoenzyme-selective inhibitors. Here, we describe fully validated human NOX inhibitors, obtained from an in silico screen, targeting the active site of Cylindrospermum stagnale NOX5 (csNOX5). The hits are validated by in vitro and in cellulo enzymatic and binding assays, and their binding modes to the dehydrogenase domain of csNOX5 studied via high-resolution crystal structures. A high-throughput screen in a panel of cancer cells shows activity in selected cancer cell lines and synergistic effects with KRAS modulators. Our work lays the foundation for the development of inhibitor-based methods for controlling the tightly regulated and highly localized ROS sources

MR-Guided High-Intensity Focused Ultrasound: Current Status of an Emerging Technology

The concept of ideal tumor surgery is to remove the neoplastic tissue without damaging adjacent normal structures. High-intensity focused ultrasound (HIFU) was developed in the 1940s as a viable thermal tissue ablation approach. In clinical practice, HIFU has been applied to treat a variety of solid benign and malignant lesions, including pancreas, liver, prostate, and breast carcinomas, soft tissue sarcomas, and uterine fibroids. More recently, magnetic resonance guidance has been applied for treatment monitoring during focused ultrasound procedures (magnetic resonance-guided focused ultrasound, MRgFUS). Intraoperative magnetic resonance imaging provides the best possible tumor extension and dynamic control of energy deposition using real-time magnetic resonance imaging thermometry. We introduce the fundamental principles and clinical indications of the MRgFUS technique; we also report different treatment options and personal outcomes