New Mechanisms of Drug Action.

With several currently marketed drugs and candidate drugs in clinical trials as a result, Chinese pharmacologists have been investigating new mechanisms of efficacy, toxicity, and resistance in an attempt to identify new functions that enable more accurate classification of drugs and their use in personalized medicine. This is especially true with respect to anticancer drugs.

Notably, Chen and colleagues pioneered the use of arsenic to treat acute promyelocytic leukemia (APL). They demonstrated that combination therapy with all-trans retinoic acid and arsenic trioxide achieved a significant remission rate (94.1%) in 85 APL patients, with a mild and reversible toxicity profile (Hu et al., 2009). This groundbreaking treatment regimen has now become the frontline therapy for de novo APL, which transforms APL into the first curable acute myeloid leukemia. Moreover, this group has further revealed that the promyelocytic leukemia protein is a direct target of arsenic trioxide (Zhang et al., 2010). Furthermore, another distinguished group of investigators led by Chen has revealed a new mechanism of drug action for adenanthin, a diterpenoid extracted from Rabdosia adenantha that induces differentiation of APL cells by directly targeting peroxidase (Liu et al., 2012).

As the new era of personalized medicines emerges, research in China concerning oncological pharmacology has recently shifted its primary focus to providing an integrative platform for the discovery and development of molecularly targeted anticancer therapies. Zhang and colleagues have demonstrated that the CUE (coupling of ubiquitin conjugation to ER degradation) domain–containing 2 (CUEDC2) protein can regulate many key cellular events, including cell cycle and inflammation (Li et al., 2008; Gao et al., 2011). Their follow-up study (Pan et al., 2011) also uncovered a crucial role that CUEDC2 can play in the progression of breast cancer, and its potential as a therapeutic target through its interaction with estrogen receptor-alpha (ER-α) protein. Collectively, these studies demonstrate that CUEDC2 serves as a new potential target for the treatments for inflammatory diseases and tumors.

New Drug Targets.

Discovery of new drug targets is the foundation for finding novel drugs in a fast, efficient, and sustainable research mode. Recently, many Chinese pharmacologists have made great strides in the discovery and functional verification of new drug targets.

The YAP/TAZ signaling pathway was initially reported as a key regulator of cell size during embryogenesis, although later investigations revealed a procarcinogenic role for this axis. Huang and colleagues provided novel evidence to show that endothelial YAP/TAZ activation induced by atheroprone-disturbed flow promotes inflammation and atherogenesis by enhancing the activity of c-Jun N-terminal kinase (Wang et al., 2016). Coincidently, several antiatherosclerotic drugs, and especially statins, can effectively inhibit the YAP/TAZ pathway, indicating that YAP/TAZ may become a potential therapeutic target against atherosclerosis.

Recently, Xiao and coworkers revealed a previously unappreciated regulatory role in necroptosis for receptor-interacting protein 3 (RIP3) and thus provided a potential therapeutic target in myocardial infarction. They discovered that the novel RIP3-Ca²⁺-calmodulin–dependent protein kinase (CaMKII)–mPTP pathway provides a potential target for the treatment of ischemia-induced and oxidative stress-induced myocardial damage (Zhang et al., 2016). With respect to hypertension, Zhu and colleagues reported that the activated transient receptor potential vanilloid 1 can induce the production of nitric oxide (NO) in endothelial cells, which may indicate a potential target for the treatment of hypertension (Yang et al., 2010).

Similar work in anticancer drug discovery has also come to fruition. Lin and colleagues (2012) revealed that activating the GSK3-TIP60-ULK1 signaling pathway can integrate protein phosphorylation and acetylation in the regulation of autophagy induced by growth-factor deprivation, thus providing a new target for antitumor drugs to regulate tumor cell autophagy. Zhao and colleagues demonstrated that the intracellular accumulation of 2-hydroxyglutarate (2-HG), an inhibitor of α-KG-dependent dioxygenases, can alter cell proliferation and growth by inhibiting the activity of dioxygenases (Xu et al., 2011). Lei and coworkers revealed that lysine-5 acetylation decreases LDH-A activity and consequently significantly inhibits cell proliferation and tumor migration, arguing that LDH-A acetylation could be targeted for the early diagnosis and treatment of pancreatic cancer (Zhao et al., 2013).

Trailblazing research in China has also brought hope to millions of patients with neuropsychiatric disorders such as anxiety and depression. Zhu and coworkers (2014) have recently shown that the binding between nNOS and carboxy-terminal PDZ ligand (CAPON) can result in the modulation of anxiety-related behaviors by regulating Dexras1-ERK signaling. They have also demonstrated that significant anxiolytic-like effects are rapidly produced by small-molecule blockers of nNOS-CAPON binding. However, the pathogenesis and molecular mechanisms of depression still remain unknown. It is noteworthy that Hu and colleagues provided convincing evidence emphasizing the roles of β-calcium/calmodulin–dependent protein kinase type II (βCaMKII) in depression (Li et al., 2013), thus verifying the lateral habenula as a new target for treatment. We believe that a deeper understanding of the mechanisms underlying anxiety will be of benefit to the development of new anxiolytic agents.

Structural Pharmacology.

With its combination of structural biology and pharmacology, structural pharmacology is emerging as a new field of pharmacological sciences and is playing an unprecedented role in the R&D of new drugs in China. Through high-resolution analysis of C-C motif chemokine receptor 5 conformation, Wu and colleagues demonstrated that HIV-1 coreceptor selectivity mainly depends on steric hindrance and charge distribution associated with residue substitutions. This result will enable structure-based drug discovery for the treatment of HIV-1 infection (Tan et al., 2013).

P2Y12 receptor (P2Y12R), a purinergic G protein-coupled receptor, plays crucial roles in platelet activation and thrombus formation. Recently, Zhao and coworkers provided detailed maps of P2Y12R crystal structure, including the 2.5-Å resolution structure of P2Y12R binding to the agonist 2MeSADP, the 3.1-Å resolution structure of P2Y12R bound to the partial agonist 2-methylthio-ATP (2MeSATP), and the 2.6-Å resolution structure of P2Y12R bound to the antagonist AZD1283. Through comparison of the structures of the three different complexes, the mechanisms involved in accelerating or slowing thrombus formation have been clearly elucidated on the basis of the interaction between receptor and drug molecules (Zhang et al., 2014a,b).

In 2013, Xu and colleagues reported a high-resolution crystal structure of human ten-eleven-translocation 2 (TET2) bound to methylated DNA. This high-resolution analysis of TET2 conformation will facilitate our understanding of the mechanisms of TET-mediated 5mC oxidation and subsequent structure-based drug discovery for myeloid leukemia (Hu et al., 2013).

Recently, cannabinoid receptor 1 (CB1) has been identified as a promising therapeutic target for many diseases, including inflammation, pain, and substance abuse disorders. To understand the mechanisms underlying the physiologic functions of CB1, and to design the next-generation of CB1-targeting drugs, a high-resolution analysis of human CB1 binding to antagonist AM6538 was reported by Liu and colleagues. These investigators showed that the CB1-AM6538 complex plays a critical role in antagonist binding (Hua et al., 2016). These lines of research will continue to unravel new modes of actions for potential drug targets.

Clinical Pharmacology.

Clinical pharmacology bridges the translation of basic research to clinical medicine. Research in clinical pharmacology is mainly focused on pharmacokinetics, pharmacodynamics, drug-drug interactions, drug resistance, pharmacogenetics, pharmacogenomics, and clinical trials of new drugs. In recent years, clinical pharmacologists in China have made great progress in clinical drug evaluation, with the aim of providing guidance for advances in rational and personalized medicine.

Zhou and colleagues (1989) are pioneers in pharmacogenetics and pharmacogenomics in China. They have reported gene polymorphisms in a number of important drug-metabolizing enzymes, drug transporters, and receptors among various Chinese ethnic groups. In the last decade, they have constructed comprehensive mathematical models and algorithms that incorporate both clinical and genetic factors to predict clinical dosages of warfarin, tacrolimus, and cisplatin, on the basis of large-sample clinical trials. These have been included in the personalized medicine guidelines published by the National Health and Family Planning Commission of China (Luo et al., 2017). Besides Zhou and colleagues, other distinguished groups are also active in clinical pharmacology research in China. Zeng and colleagues were the first to develop recombinant drug-metabolizing enzymes and cell models with stably overexpressed drug transporters for studies of drug metabolism and pharmacokinetics in China. The tools that they have provided include more than 50 human recombinant enzymes, such as cytochrome P450s, UGTs, GSHs, ADH, and AKR, as well as ∼30 cell lines with stably overexpressed drug transporters, such as MDR1, BCRP, organic cation transporters (OCTs), OATs, and MRPs. Recently, research in this group has focused on the epigenetic mechanisms responsible for the silencing of drug transporters in cancer cells. They have reported that aberrant DNA methylation surrounding the human OCT2 promoter could be responsible for OCT2 repression in renal cell carcinoma, thus providing proof-of-concept for novel targeted therapies (Liu et al., 2016). Zhong and colleagues (2016) have used a genome-wide association study to identify new genetic loci that modify antiplatelet effects in Chinese patients with coronary heart disease. In a randomized, double-blind clinical trial with 20,702 adult hypertensive patients, Huo and colleagues (2015) revealed that the combined use of enalapril and folic acid could significantly reduce the risk of first stroke, when compared with enalapril alone.

Antibiotic resistance is one of the major issues that requires the constant attention of clinical pharmacologists. Glycopeptides, including vancomycin and teicoplainin, have broad activities against Gram-positive bacteria and are usually considered for the treatment of life-threatening infections induced by Gram-positive pathogens. VanA and vanB are usually considered the two predominant genotypes of vancomycin-resistant enterococci worldwide. In 2010, a new glycopeptide-resistant genotype, VanM, was found by Wang and colleagues in a clinical strain of Enterococcus faecium Efm-HS0661 in Shanghai. Like the VanA type, VanM confers high-level resistance to glycopeptides (Xu et al., 2010). Recently, a new statistical analysis was reported by the same research group showing that VanM (64.3%, 45/70) was more prevalent than VanA (35.7%, 25/70) in 70 vancomycin-resistant enterococci strains collected from nine hospitals in Shanghai during 2006–2014 (Chen et al., 2015).