Roles and drug development of METTL3 (methyltransferase-like 3) in anti-tumor therapy.

Methyltransferase complex, such as METTL3/METTL14/WTP, catalyze N6-methyladenosine (m6A), which is the most abundant mRNA modification in mammals. Besides acting as a m6A methyltransferase, METTL3 also regulates mRNA translation and other biological processes. Studies have identified numerous roles and molecular mechanisms associated with METTL3 in multiple biological processes especially in tumors in recent years. Furthermore, targeting METTL3 as an efficient therapeutic way for the treatment of different kinds of tumors has gained a lot of attention. However, these findings and researches have not been summarized. In this review, the most recent important roles of METTL3 in various tumors including acute myeloid leukemia, lung cancer, breast cancer, liver cancer, gastric cancer, pancreatic cancer, colorectal cancer, bladder cancer, prostate cancer and glioblastoma were systematically summarized. In addition, disclosed METTL3 inhibitors recently were also summarized and discussed for medicinal chemists investigating METTL3 inhibitors with different skeleton structures for the application of human cancer therapy.

Discovery of imidazopyrrolopyridines derivatives as novel and selective inhibitors of JAK2.

Herein, we describe the design, synthesis, and structure-activity relationships of a series of imidazopyrrolopyridines derivatives that selectively inhibit Janus kinase 2 (JAK2). These screening cascades revealed that 6k was a preferred compound, with IC50 values of 10 nM for JAK2. Moreover, 6k was a selective JAK2 inhibitor with 19-fold, >30-fold and >30-fold selectivity over JAK1, JAK3 and TYK2 respectively. In cytokine-stimulated cell-based assays, 6k exhibited a higher JAK2 selectivity over JAK1 isoforms. Indeed, at a dose of 20 mg/kg compound 6k, pSTAT3 and pSTAT5 expression was reduced to levels comparable to those of control animals untreated with GM-CSF. Additionally, 6k showed a relatively good bioavailability (F = 38%), a suitable half-life time (T1/2 = 1.9 h), a satisfactory metabolic stability, suggesting that 6k might be a promising inhibitor of JAK2 for further development research for the treatment of MPNs.

Janus kinases (JAKs): The efficient therapeutic targets for autoimmune diseases and myeloproliferative disorders.

The Janus kinases or JAKs are a family of intracellular tyrosine kinases that play an essential role in the signaling of numerous cytokines that have been implicated in the pathogenesis of autoimmune diseases and myeloproliferative disorders. JAKs are activated upon ligand induced receptor homo- or heterodimerization, which results in the immediate phosphorylation of tyrosine residues and the phosphotyrosines then serve as docking sites for cytoplasmic signal transducer and activator of transcription (STAT) proteins which become phosphorylated by the JAKs upon recruitment to the receptor complex. The phosphorylated STAT proteins dimerize and travel to the cellular nucleus, where they act as transcription factors. Interfering in the JAK-STAT pathway has yielded the only approved small molecule kinase inhibitors for immunological indications. Numerous medicinal chemistry studies are currently aimed at the design of novel and potent inhibitors for JAKs. Additionally, whether the second-generation inhibitors which possessed selectivity for JAKs are more efficient are under research. This Perspective summarizes the progress in the discovery and development of JAKs inhibitors, including the potential binding site and approaches for identifying small-molecule inhibitors, as well as future therapeutic perspectives in autoimmune diseases and myeloproliferative disorders are also put forward in order to provide reference and rational for the drug discovery of novel and potent JAKs inhibitors.

Discovery of pyridine tetrahydroisoquinoline thiohydantoin derivatives with low blood-brain barrier penetration as the androgen receptor antagonists.

Prostate cancer (PC) is the most diagnosed type of malignancy in men and the major frequently cause of cancer-related death worldwide. The androgen receptor (AR) has become a promising drug target for the treatment of PC. Here, we reported the design, optimization and evaluation of pyridine tetrahydroisoquinoline thiohydantoin derivatives with improved activity and safety as potent AR antagonists. The most promising compound 42f exhibited potent inhibitory activity on AR and strongly blocked AR nuclear translocation. Moreover, 42f displayed promising in vitro antitumor activity toward AR-dependent prostate cancer cell lines (LNCaP) and also demonstrated therapeutic effects in LNCaP xenograft tumor model in mice (TGI: 79%) with no apparent toxicity observed in vivo. More importantly, 42f showed negligible penetration of the brain-blood barrier (BBB) compared with enzalutamide. These results provide a foundation for the development of a new class of androgen receptor antagonists for potential therapeutics against PC with lower seizurogenic risk for patients.

Exploring the tetrahydroisoquinoline thiohydantoin scaffold blockade the androgen receptor as potent anti-prostate cancer agents.

Prostate cancer (PC) is a major cause of cancer-related male death in worldwide and the identification of new and improved potent anti-PC molecules is constantly required. A novel scaffold of tetrahydroisoquinoline thiohydantoin was rationally designed based on the enzalutamide structures and our pre-work, leading to the discovery of a series of new antiproliferative compounds. Several new analogues displayed improved androgen receptor (AR) antagonistic activity, while maintaining the higher selective toxicity toward LNCaP cells (AR-rich) versus DU145 cells (AR-deficient) compared to enzalutamide. In fact, compound 55 exhibited promising in vitro antitumor activity by impairing AR unclear translocation. More importantly, 55 showed better pharmacokinetic properties compared to the compound 1 reported in our pre-work. These results demonstrate a step towards the development of novel and improved AR antagonists.

Current knowledge on the nucleotide agonists for the P2Y2 receptor.

P2Y receptors are G-protein-coupled receptors (GPCRs) for extracellular nucleotides. There are eight mammalian P2Y receptor subtypes (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14). P2Y2 receptors are widely expressed and play important roles in multiple functionalities. Diquafosol tetrasodium, known as INS365, which was the first P2Y2 receptor agonists that had been approved in April 2010 and launched in Japan by Santen Pharmaceuticals. Besides, a series of similar agonists for the P2Y2 receptor are undergoing development to cure different diseases related to the P2Y2 receptor. This article illustrated the structure and functions of the P2Y2 receptor and focused on several kinds of agonists about their molecular structures, research progress and chemical synthesis methods. Last but not the least, we summarized the structures-activity relationship (SAR) of agonists for the P2Y2 receptor and expected more efficient agonists for the P2Y2 receptor.

Degradation of Androgen Receptor through Small Molecules for Prostate Cancer.

Prostate cancer is the most common carcinoma among aged males in western countries and more aggressive and lethal castration resistant prostate cancer often occurs after androgen deprivation therapy. The high expression of androgens and androgen receptor is closely related to prostate cancer. Efficient androgen receptor antagonists, such as enzalutamide and ARN-509, could be employed as potent anti-prostate cancer agents. Nevertheless, recent studies have revealed that F876L mutation in androgen receptor converts the action of enzalutamide and ARN-509 from an antagonist to agonist, so that novel strategies are urgent to address this resistance mechanism. In this review, we focus on the discussion about some novel strategies, which targets androgen receptor mainly through the degrading pathway as potential treatments for prostate cancer.

Discovery and synthesis of novel Wogonin derivatives with potent antitumor activity in vitro.

Phenotypic screening of high quality compound library is one of the most effective strategy to obtain novel bioactive compounds. Recently, our group have constructed a Wogonin-scaffold library with substituents diversity and successfully obtained a series of potent compounds. Herein, we reported the synthesis of these compounds and evaluated the in vitro antitumor activity against a panel of human tumor cell lines. Most of them showed good activity with a broad spectrum and preliminary structure-activity relationship for the substitutions were obtained. Further biological assays showed that the most potent compounds 18n and 20b could significantly enhance the intracellular ROS level and induce the cell apoptosis at low micromole level. Through similarity searching, CDK9 was identified as the potential target for 20b, which could be a start point for next structure-based drug design.

Design and synthesis of indoline thiohydantoin derivatives based on enzalutamide as antiproliferative agents against prostate cancer.

A novel scaffold of indoline thiohydantoin was discovered as potent androgen receptor (AR) antagonist through rational drug designation. Several compounds showed good biological profiles in AR binding and higher selective toxicity than enzalutamide toward LNCaP cells (AR-rich) versus DU145 cells (AR-deficient). In addition, the docking studies supported the rationalization of the biological evaluation. Among these compounds, the representative compound 48c exhibited the strongest inhibitory effect on LNCaP growth and also acted as a competitive AR antagonist. Further preliminary mechanism study confirmed that 48c exerted its AR antagonistic activity through impairing AR nuclear translocation. All these results indicated that the novel scaffold compounds demonstrated AR antagonistic behavior and promising candidates for future development were identified.

Synthesis and biological evaluation of 6-fluoro-3-phenyl-7-piperazinyl quinolone derivatives as potential topoisomerase I inhibitors.

The design and synthesis of a new series of 6-fluoro-3-phenyl-7-piperazinyl quinolone derivatives, built on the structure of 1-ethyl-3-(6-nitrobenzoxazol-2-yl)-6,8-difluoro-7-(3-methylpiperazin-1-yl)-4(1H)-quinolone, are described. These compounds provide new scaffold for the discovery of Topoisomerase I (Top I) inhibitors and target based assay showed that they can obviously inhibited Top I at 100 µM. The in vitro anti-proliferative activity of these new compounds was evaluated against A549, Hela, BGC-823, and HepG2 cell lines. Compounds 18a-g showed potent inhibitory activity against the growth of those cancer cell lines. The most positive compounds 18f and 18g demonstrated as potent as camptothecin in Top I inhibition assay and MTT assay. Compounds 18f and 18g led to an obvious increase in the percentage of S phase of the cells in 24 h. The in vivo data showed that 18f and 18g inhibited tumor growth with the inhibitory rate of 29.25% and 42.75% at 20 mg/kg, respectively. The data suggested the therapeutic potential for further development.

Progress in the mechanism and drug development of castration-resistant prostate cancer.

Although prostate cancer can initially respond to androgen deprivation therapy, it will inevitably relapse and switch to a castration-resistant state. The progress in understanding the mechanism of castration-resistant prostate cancer (CRPC) has led to the evolution of novel agents, including sipuleucel-T as an immunomodulant agent, enzalutamide as an androgen receptor antagonist, docetaxel as a chemotherapeutic agent and radium-223 as a radiopharmaceutical agent. In this review, we discuss the main mechanisms of CRPC and the development of promising agents along with the novel therapies in the clinic. New therapeutic challenges remain, such as the identification of predictive biomarkers and the optimal combinations of agents. Future investigation is still needed for a better understanding of CRPC.