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The PI3K-AKT-mTOR pathway is one of the most frequently dysregulated pathways in cancer and, consequently, more than 40 compounds that target key components of this signalling network have been tested in clinical trials involving patients with a range of different cancers. The clinical development of many of these agents, however, has not advanced to late-phase randomized trials, and the antitumour activity of those that have been evaluated in comparative prospective studies has typically been limited, or toxicities were found to be prohibitive. Nevertheless, the mTOR inhibitors temsirolimus and everolimus and the PI3K inhibitors idelalisib and copanlisib have been approved by the FDA for clinical use in the treatment of a number of different cancers. Novel compounds with greater potency and selectivity, as well as improved therapeutic indices owing to reduced risks of toxicity, are clearly required. In addition, biomarkers that are predictive of a response, such as PIK3CA mutations for inhibitors of the PI3K catalytic subunit α isoform, must be identified and analytically and clinically validated. Finally, considering that oncogenic activation of the PI3K-AKT-mTOR pathway often occurs alongside pro-tumorigenic aberrations in other signalling networks, rational combinations are also needed to optimize the effectiveness of treatment. Herein, we review the current experience with anticancer therapies that target the PI3K-AKT-mTOR pathway.

A large proportion of biomedical research and the development of therapeutics is focused on a small fraction of the human genome. In a strategic effort to map the knowledge gaps around proteins encoded by the human genome and to promote the exploration of currently understudied, but potentially druggable, proteins, the US National Institutes of Health launched the Illuminating the Druggable Genome (IDG) initiative in 2014. In this article, we discuss how the systematic collection and processing of a wide array of genomic, proteomic, chemical and disease-related resource data by the IDG Knowledge Management Center have enabled the development of evidence-based criteria for tracking the target development level (TDL) of human proteins, which indicates a substantial knowledge deficit for approximately one out of three proteins in the human proteome. We then present spotlights on the TDL categories as well as key drug target classes, including G protein-coupled receptors, protein kinases and ion channels, which illustrate the nature of the unexplored opportunities for biomedical research and therapeutic development.

Acute nociceptive pain is a key defence system that enables the detection of danger signals that threaten homeostasis and survival. However, chronic pain (such as the neuropathic pain that occurs after peripheral nerve injury) is not simply a consequence of the continuity of acute nociceptive signals but rather of maladaptive nervous system function. Over recent decades, studies have provided evidence for the necessity and sufficiency of microglia for the alterations in synaptic remodelling, connectivity and network function that underlie chronic pain and have shed light on the underlying molecular and cellular mechanisms. It is also becoming clear that microglia have active roles in brain regions important for the emotional and memory-related aspects of chronic pain. Recent advances in the development of new drugs targeting microglia and the establishment of new sources of human microglia-like cells may facilitate translation of these findings from bench to bedside.

Refinements in the chemistries employed in oligonucleotide therapeutics have galvanized clinical progress. The complex interplay between chemical modifications and integration into sequence architecture is discussed in the context of antisense and small-interfering RNA drugs. After nearly 40 years of development, oligonucleotide therapeutics are nearing meaningful clinical productivity. One of the key advantages of oligonucleotide drugs is that their delivery and potency are derived primarily from the chemical structure of the oligonucleotide whereas their target is defined by the base sequence. Thus, as oligonucleotides with a particular chemical design show appropriate distribution and safety profiles for clinical gene silencing in a particular tissue, this will open the door to the rapid development of additional drugs targeting other disease-associated genes in the same tissue. To achieve clinical productivity, the chemical architecture of the oligonucleotide needs to be optimized with a combination of sugar, backbone, nucleobase, and 3′- and 5′-terminal modifications. A portfolio of chemistries can be used to confer drug-like properties onto the oligonucleotide as a whole, with minor chemical changes often translating into major improvements in clinical efficacy. One outstanding challenge in oligonucleotide chemical development is the optimization of chemical architectures to ensure long-term safety. There are multiple designs that enable effective targeting of the liver, but a second challenge is to develop architectures that enable robust clinical efficacy in additional tissues.

A few commonly used non-antibiotic drugs have recently been associated with changes in gut microbiome composition, but the extent of this phenomenon is unknown. Here, we screened more than 1,000 marketed drugs against 40 representative gut bacterial strains, and found that 24% of the drugs with human targets, including members of all therapeutic classes, inhibited the growth of at least one strain in vitro . Particular classes, such as the chemically diverse antipsychotics, were overrepresented in this group. The effects of human-targeted drugs on gut bacteria are reflected on their antibiotic-like side effects in humans and are concordant with existing human cohort studies. Susceptibility to antibiotics and human-targeted drugs correlates across bacterial species, suggesting common resistance mechanisms, which we verified for some drugs. The potential risk of non-antibiotics promoting antibiotic resistance warrants further exploration. Our results provide a resource for future research on drug–microbiome interactions, opening new paths for side effect control and drug repurposing, and broadening our view of antibiotic resistance. A screen of more than 1,000 drugs shows that about a quarter of the non-antibiotic drugs inhibit the growth of at least one commensal bacterial strain in vitro . Non-antibiotics with antibiotic effects Some non-antibiotic drugs have been associated with changes in gut microbiome composition, but the extent of this phenomenon is unknown. Athanasios Typas and colleagues screened more than 1,000 marketed drugs and observed that a quarter of them inhibited the growth of at least one bacterial strain in vitro . Scrutiny of previous human cohort studies showed that human-targeted drugs with anticommensal activity have antibiotic-like side effects in humans. The new data provide a resource for future drug-therapy research.

Genetic defects underlying the melanocortin-4 receptor (MC4R) signaling pathway lead to severe obesity. Three severely obese LEPR-deficient individuals were administered the MC4R agonist setmelanotide, resulting in substantial and durable reductions in hyperphagia and body weight over an observation period of 45–61 weeks. Compared to formerly developed and tested MC4R agonists, setmelanotide has the unique capability of activating nuclear factor of activated T cell (NFAT) signaling and restoring function of this signaling pathway for selected MC4R variants. Our data demonstrate the potency of setmelanotide in treatment of individuals with diverse MC4R-related pathway deficiencies. Treatment with setmelanotide, a new-generation MC4R agonist, provides durable weight loss in hyperphagic, leptin receptor–deficient patients, suggesting a pharmacological avenue to treat patients with various MC4R pathway defects.

Immune checkpoint blockade (ICB) has demonstrated curative potential in several types of cancer, but only for a small number of patients. Thus, the identification of reliable and noninvasive biomarkers for predicting ICB responsiveness is an urgent unmet need. Here, we show that ICB increased tumor vessel perfusion in treatment-sensitive EO771 and MMTV-PyVT breast tumor as well as CT26 and MCA38 colon tumor models, but not in treatment-resistant MCaP0008 and 4T1 breast tumor models. In the sensitive tumor models, the ability of anti-cytotoxic T lymphocyte-associated protein 4 or anti-programmed cell death 1 therapy to increase vessel perfusion strongly correlated with its antitumor efficacy. Moreover, globally enhanced tumor vessel perfusion could be detected by Doppler ultrasonography before changes in tumor size, which predicted final therapeutic efficacy with more than 90% sensitivity and specificity. Mechanistically, CD8+ T cell depletion, IFN-γ neutralization, or implantation of tumors in IFN-γ receptor knockout mice abrogated the vessel perfusion enhancement and antitumor effects of ICB. These results demonstrated that ICB increased vessel perfusion by promoting CD8+ T cell accumulation and IFN-γ production, indicating that increased vessel perfusion reflects the successful activation of antitumor T cell immunity by ICB. Our findings suggest that vessel perfusion can be used as a novel noninvasive indicator for predicting ICB responsiveness.

An X-ray structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone reveals an extended binding pocket and indicates structural features that could be used to design drugs that specifically target the D2 receptor. Dopamine's unusual binding technique D2 dopamine receptors are the principal targets for antipsychotic drugs for the treatment of schizophrenia, and offer possibilities for treating depression and Parkinson's disease. However, molecular-level understanding of these receptors is limited, and many available drugs cause serious side-effects as a result of activity at other dopamine receptors. Here, Bryan Roth and colleagues report the crystal structure of the D2 receptor in complex with the antipsychotic drug risperidone. This structure shows an unusual binding mode of the drug, distinct from those observed in the related D3 and D4 receptors, whereby a hydrophobic patch formed by a tryptophan residue regulates the entry and exit of the drug. Mutation at this position reduces the drug residence time, which is believed to be related to side-effects of common antipsychotics. This work hints at ways to develop safer antipsychotic drugs that are selective for D2. Dopamine is a neurotransmitter that has been implicated in processes as diverse as reward, addiction, control of coordinated movement, metabolism and hormonal secretion. Correspondingly, dysregulation of the dopaminergic system has been implicated in diseases such as schizophrenia, Parkinson’s disease, depression, attention deficit hyperactivity disorder, and nausea and vomiting. The actions of dopamine are mediated by a family of five G-protein-coupled receptors 1 . The D2 dopamine receptor (DRD2) is the primary target for both typical 2 and atypical 3 , 4 antipsychotic drugs, and for drugs used to treat Parkinson’s disease. Unfortunately, many drugs that target DRD2 cause serious and potentially life-threatening side effects due to promiscuous activities against related receptors 4 , 5 . Accordingly, a molecular understanding of the structure and function of DRD2 could provide a template for the design of safer and more effective medications. Here we report the crystal structure of DRD2 in complex with the widely prescribed atypical antipsychotic drug risperidone. The DRD2–risperidone structure reveals an unexpected mode of antipsychotic drug binding to dopamine receptors, and highlights structural determinants that are essential for the actions of risperidone and related drugs at DRD2.

The unfolded protein response (UPR) is a cellular homeostatic mechanism that is activated in many human cancers and plays pivotal roles in tumor progression and therapy resistance. However, the molecular mechanisms for UPR activation and regulation in cancer cells remain elusive. Here, we show that oncogenic MYC regulates the inositol-requiring enzyme 1 (IRE1)/X-box binding protein 1 (XBP1) branch of the UPR in breast cancer via multiple mechanisms. We found that MYC directly controls IRE1 transcription by binding to its promoter and enhancer. Furthermore, MYC forms a transcriptional complex with XBP1, a target of IRE1, and enhances its transcriptional activity. Importantly, we demonstrate that XBP1 is a synthetic lethal partner of MYC. Silencing of XBP1 selectively blocked the growth of MYC-hyperactivated cells. Pharmacological inhibition of IRE1 RNase activity with small molecule inhibitor 8866 selectively restrained the MYC-overexpressing tumor growth in vivo in a cohort of preclinical patient-derived xenograft models and genetically engineered mouse models. Strikingly, 8866 substantially enhanced the efficacy of docetaxel chemotherapy, resulting in rapid regression of MYC-overexpressing tumors. Collectively, these data establish the synthetic lethal interaction of the IRE1/XBP1 pathway with MYC hyperactivation and provide a potential therapy for MYC-driven human breast cancers.

Cucurbitacins which are structurally diverse triterpenes found in the members of Cucurbitaceae and several other plant families possess immense pharmacological potential. This diverse group of compounds may prove to be important lead molecules for future research. Research focused on these unattended medicinal leads from the nature can prove to be of immense significance in generating scientifically validated data with regard to their efficacy and possible role in various diseases. This review is aimed to provide an insight into the chemical nature and medicinal potential of these compounds exploring their proposed mode of action, probable molecular targets and to have an outlook on future directions of their use as medicinal agents.