The Development of HDAC and Tubulin Dual-Targeting Inhibitors for Cancer Therapy.

Histone deacetylases (HDACs) are a class of enzymes that are responsible for the removal of acetyl groups from the ε-N-acetyl lysine of histones, allowing histones to wrap DNA more tightly. HDACs play an essential role in many biological processes, such as gene regulation, transcription, cell proliferation, angiogenesis, migration, differentiation and metastasis, which make it an excellent target for anticancer drug discovery. The search for histone deacetylase inhibitors (HDACis) has been intensified, with numerous HDACis being discovered, and five of them have reached the market.

Development of VER-50589 analogs as novel Hsp90 inhibitors.

As an important target for tumor therapy, heat shock protein 90 has attracted tremendous attention. Through structure analysis, we rationally designed three analogs of VER-50589 which is a known and potent Hsp90 inhibitor. Target inhibitory activity result showed that one compound dubbed as 12-1 exhibited strong inhibitory activity against Hsp90 with an IC value of 9 nM.

Cost-effectiveness of fuzuloparib compared to routine surveillance, niraparib and olaparib for maintenance treatment of patients with germline BRCA1/2 mutation and platinum-sensitive recurrent ovarian carcinoma in China.

Maintenance therapy with the poly (ADP-ribose) polymerase inhibitors (PARPis) for platinum-sensitive recurrent ovarian carcinoma (OC) have proven to be effective compared with placebo. We aimed to evaluate the cost-effectiveness (CE) of maintenance fuzuloparib compared to routine surveillance (RS), niraparib and olaparib for platinum-sensitive recurrent OC from the Chinese healthcare systems. A partitioned survival model with three-state (progression-free, progressed, death) was constructed utilizing TreeAge Pro 2011 software to evaluate the economic value of fuzuloparib, niraparib and olaparib maintenance treatment for platinum-sensitive recurrent OC based on the clinical data derived from FZOCUS-2, ENGOT-OV16/NOVA and ENGOT-Ov21/SOLO2.

WRQ-2, a gemcitabine prodrug, reverses gemcitabine resistance caused by hENT1 inhibition.

Gemcitabine is widely used in the clinic as a first-line antitumor agent. However, intrinsic and acquired resistance hinders its wide clinical application. In this study, a gemcitabine prodrug nominated as WRQ-2 was designed and synthesized by conjugating gemcitabine with the indole-3-methanol analogue OSU-A9 through a carbamate linkage.

Hybrid Histone Deacetylase Inhibitor: An Effective Strategy for Cancer Therapy.

Inhibition of histone deacetylases (HDACs) has proven to be an effective strategy for cancer therapy. To date, five histone deacetylase inhibitors (HDACis) have been approved for cancer treatment, and numerous others are undergoing clinical trials. An agent that can simultaneously and effectively inhibit two or more targets may offer greater therapeutic benefits over single-acting agents in preventing resistance to treatment and potentiating synergistic effects.

Design, synthesis and antitumor activity study of a gemcitabine prodrug conjugated with a HDAC6 inhibitor.

Gemcitabine, as a first-line antitumor drug, has attracted extensive attention. However the occurrence of drug resistance limits its clinical utilization. In this paper, a gemcitabine prodrug GZ was designed and synthesized by conjugation of gemcitabine with a newly reported HDAC6 selective inhibitor pentadecanoic acid.

Design, synthesis and antitumor activity study of PARP-1/HDAC dual targeting inhibitors.

Both poly(ADP-ribose)polymerase-1 (PARP-1) and histone deacetylase (HDAC) are important antitumor targets and have attracted extensive attention. In this work, a total of fourteen PARP-1/HDAC dual targeting inhibitors were designed and synthesized using either benzopyrazole or benzimidazole as core structures. Two leading compounds 1-8-6 and 1-8-7 were proven to be dual targeting inhibitors of PARP-1 and HDAC6, and showed high antiproliferative activities against six human cancer cell lines with IC values in micromole range.

The design and synthesis of transient receptor potential vanilloid 3 inhibitors with novel skeleton.

Transient receptor potential vanilloid 3 (TRPV3) channel as a member of thermo TRPV subfamily is primarily expressed in the keratinocytes of the skin and sensory neurons, and plays critical roles in various physiological and pathological processes such as inflammation, pain sensation and skin disorders. However, TRPV3 studies have been challenging, in part due to a lack of research tools such as selective antagonists. Recently, we synthesized a series of cinnamate ester derivatives and evaluated their inhibitory activities on human TRPV3 channels expressed in HEK293 cells using whole-cell patch clamp recordings.

Design, synthesis and antitumor activity evaluation of novel HDAC inhibitors with tetrahydrobenzothiazole as the skeleton.

HDACs as important targets for cancer therapy have attracted extensive attentions. In this work, a series of sixteen hydroxamic acid based HDAC inhibitors were designed and synthesized with 4,5,6,7-tetrahydrobenzothiazole as the structural core. Majority of them exhibited potent inhibitory activities against HDACs and one leading compound 6h was dug out.

Novel histone deacetylase inhibitors bearing a 4-piperidin-4-yl-triazole scaffold as antitumor agents.

Histone deacetylases have proven to be promising targets for the development of anticancer drugs. In this work, we reported the design and synthesis of a series of 20 novel hydroxamic acid-based histone deacetylase inhibitors with 4-piperidin-4-yl-triazole as the core structure. Five newly obtained compounds displayed excellent HDAC6 inhibitory activities.

Drugs for the Treatment of Zika Virus Infection.

Zika virus is an emerging flavivirus that causes the neurodevelopmental congenital Zika syndrome and that has been linked to the neuroinflammatory Guillain-Barré syndrome. The absence of a vaccine or a clinically approved drug to treat the disease combined with the likelihood that another outbreak will occur in the future defines an unmet medical need. Several promising drug candidate molecules have been reported via repurposing studies, high-throughput compound library screening, and de novo design in the short span of a few years.

Small Molecular Gemcitabine Prodrugs for Cancer Therapy.

Gemcitabine as a pyrimidine nucleoside analog anticancer drug has high efficacy for a broad spectrum of solid tumors. Gemcitabine is activated within tumor cells by sequential phosphorylation carried out by deoxycytidine kinase to mono-, di-, and triphosphate nucleotides with the last one as the active form. But the instability, drug resistance and toxicity severely limited its utilization in clinics.

Anti-tumor activity evaluation of novel tubulin and HDAC dual-targeting inhibitors.

Histone deacetylases (HDACs) have proven to be promising targets for the development of anti-cancer drugs. In this study, we reported a series of novel chalcone based tubulin and HDAC dual-targeting inhibitors. Three compounds inhibited the activities of HDAC and tubulin polymerization simultaneously and displayed anti-proliferative activities toward eleven human tumor cell lines.

Design and synthesis of novel histone deacetylase 6 inhibitors with benzyl-triazole as the core skeleton.

In the field of epigenetics, histone deacetylases (HDACs) are important members and well validated targets for anti-cancer drugs discovery. In this study, we designed and synthesized twenty-seven novel hydroxamic acid-based HDAC inhibitors (HDACis) with benzyl-triazole as the core skeleton. Most target compounds displayed excellent inhibition rates toward HDACs.

Design, synthesis and biological evaluation of 4-piperidin-4-yl-triazole derivatives as novel histone deacetylase inhibitors.

Histone deacetylase is an important member of epigenetics and a well validated target for anti-cancer drug discovery. In this study, we designed and synthesized a series of twenty-one novel hydroxamic acid-based histone deacetylase inhibitors with 4-piperidin-4-yl-triazole as the core skeleton. Most target compounds displayed excellent inhibition rates toward histone deacetylases at the concentration of 1 μM.

Novel HDAC6 selective inhibitors with 4-aminopiperidine-1- carboxamide as the core structure enhanced growth inhibitory activity of bortezomib in MCF-7 cells.

In epigenetics, histone deacetylases (HDACs) are well validated targets for the development of anticancer drugs. In this work, we reported the design and synthesis of a series of twenty two novel (E)-N-hydroxycinnamamide-based HDAC inhibitors with 4-aminopiperidine1-carboxamide as the core structure. Most newly synthesized compounds displayed high inhibition rates toward HDAC at the concentration of 1 μM.

Aspergiolides A and B: Core Structural Establishment and Synthesis of Structural Analogues.

The core structure of marine natural products aspergiolides A (1a) and B (1b) was achieved via a concise, two-step procedure with satisfactory yield. Based on this protocol, a natural products mimic library containing 25 structural simplified analogues of 1a was then constructed. Several prepared analogues showed potential cytotoxic activity against five different tumor cell lines, and compound 7bb, in particular, exhibited cytotoxicity comparable to that of 1a.

Kinase and Histone Deacetylase Hybrid Inhibitors for Cancer Therapy.

Histone deacetylases (HDACs), encompassing at least 18 members, are promising targets for anticancer drug discovery and development. To date, five histone deacetylase inhibitors (HDACis) have been approved for cancer treatment, and numerous others are undergoing clinical trials. It has been well validated that an agent that can simultaneously and effectively inhibit two or more targets may offer greater therapeutic benefits over single-acting agents in preventing resistance to treatment and in potentiating synergistic effects.

Tip60: Main Functions and Its Inhibitors.

Background: Tip60, the founding member of MYST histone acetyltransferase family, was originally identified as a cellular acetyltransferase protein that interacts with HIV-1 Tat. Tip60 plays roles in many processes such as cellular signaling transmission, DNA damage repair, cell cycle and checkpoint control and apoptosis by acetylating its histone or non-histone substrates.

Results: Dysfunction of Tip60 could promote or suppress diseases including different kinds of cancers.

Discovery of N-hydroxy-4-(1H-indol-3-yl)butanamide as a histone deacetylase inhibitor.

The indoles plant growth hormones have exhibited potentially antitumor activities. However, the targets of these indoles have not been clearly elucidated. By introduction of hydroxamic acid group to the structure of indolebutyric acid, the derived molecule (IBHA) exhibited potent HDAC2 (IC50 value of 0.

Design of a fluorescent ligand targeting the S-adenosylmethionine binding site of the histone methyltransferase MLL1.

The histone methyltransferase MLL1 has been linked to translocation-associated gene fusion in childhood leukemias and is an attractive drug target. High-throughput biochemical analysis of MLL1 methyltransferase activity requires the production of at least a trimeric complex of MLL1, RbBP5 and WDR5 to elicit robust activity. Production of trimeric and higher order MLL1 complexes in the quantities and reproducibility required for high-throughput screening presents a significant impediment to MLL1 drug discovery efforts.

Integration of Bioorthogonal Probes and Q-FRET for the Detection of Histone Acetyltransferase Activity.

Histone acetyltransferases (HATs) are key players in the epigenetic regulation of gene function. The recent discovery of diverse HAT substrates implies a broad spectrum of cellular functions of HATs. Many pathological processes are also intimately associated with the dysregulation of HAT levels and activities.

Eleganketal A, a highly oxygenated dibenzospiroketal from the marine-derived fungus Spicaria elegans KLA03.

Eleganketal A (1), a naturally occurring aromatic polyketide possessing a rare highly oxygenated spiro[isobenzofuran-1,3'-isochroman] ring system, was isolated from the fungus Spicaria elegans KLA03 by culturing it in a modified mannitol-based medium. The structure of 1 including the absolute configuration was determined by combining spectroscopic analysis, synthesis of the racemic permethylated analogue, chiral-phase HPLC separation, and TDDFT-ECD analysis.

Isolation and photoinduced conversion of 6-epi-stephacidins from Aspergillus taichungensis.

Three prenylated indole alkaloids with a rare anti bicyclo-[2.2.2]diazaoctane core ring (5-7) were isolated from Aspergillus taichungensis.

Lysosomotropic properties of weakly basic anticancer agents promote cancer cell selectivity in vitro.

Drug distribution in cells is a fundamentally important, yet often overlooked, variable in drug efficacy. Many weakly basic anticancer agents accumulate extensively in the acidic lysosomes of normal cells through ion trapping. Lysosomal trapping reduces the activity of anticancer drugs, since anticancer drug targets are often localized in the cell cytosol or nucleus.