Polycomb repressive complex 2 (PRC2) has been shown to play a major role in transcriptional silencing in part by installing methylation marks on lysine 27 of histone 3. Dysregulation of PRC2 function ...correlates with certain malignancies and poor prognosis. EZH2 is the catalytic engine of the PRC2 complex and thus represents a key candidate oncology target for pharmacological intervention. Here we report the optimization of our indole-based EZH2 inhibitor series that led to the identification of CPI-1205, a highly potent (biochemical IC50 = 0.002 μM, cellular EC50 = 0.032 μM) and selective inhibitor of EZH2. This compound demonstrates robust antitumor effects in a Karpas-422 xenograft model when dosed at 160 mg/kg BID and is currently in Phase I clinical trials. Additionally, we disclose the co-crystal structure of our inhibitor series bound to the human PRC2 complex.
The eight contributions here provide ample evidence that shape as a volume or as a surface is a vibrant and useful concept when applied to drug discovery. It provides a reliable scaffold for ..."decoration" with chemical intuition (or bias) for virtual screening and lead optimization but also has its unadorned uses, as in library design, ligand fitting, pose prediction, or active site description. Computing power has facilitated this evolution by allowing shape to be handled precisely without the need to reduce down to point descriptors or approximate metrics, and the diversity of resultant applications argues for this being an important step forward. Certainly, it is encouraging that as computation has enabled our intuition, molecular shape has consistently surprised us in its usefulness and adaptability. The first Aurelius question, "What is the essence of a thing?", seems well answered, however, the third, "What do molecules do?", only partly so. Are the topics covered here exhaustive, or is there more to come? To date, there has been little published on the use of the volumetric definition of shape described here as a QSAR variable, for instance, in the prediction or classification of activity, although other shape definitions have been successful applied, for instance, as embodied in the Compass program described above in "Shape from Surfaces". Crystal packing is a phenomenon much desired to be understood. Although powerful models have been applied to the problem, to what degree is this dominated purely by the shape of a molecule? The shape comparison described here is typically of a global nature, and yet some importance must surely be placed on partial shape matching, just as the substructure matching of chemical graphs has proved useful. The approach of using surfaces, as described here, offers some flavor of this, as does the use of metrics that penalize volume mismatch less than the Tanimoto, e.g., Tversky measures. As yet, there is little to go on as to how useful a paradigm this will be because there is less software and fewer concrete results.Finally, the distance between molecular shapes, or between any shapes defined as volumes or surfaces, is a metric property in the mathematical sense of the word. As yet, there has been little, if any, application of this observation. We cannot know what new application to the design and discovery of pharmaceuticals may yet arise from the simple concept of molecular shape, but it is fair to say that the progress so far is impressive.
Highlights • There is a clear case for development of vaccines against S. pyogenes given the large disease burden. • The biological feasibility of vaccines against S. pyogenes is well supported. • ...There are multiple vaccine candidates in clinical and pre-clinical development.
A 26-residue peptide BimBH3 binds indiscriminately to multiple oncogenic Bcl2 proteins that regulate apoptosis of cancer cells. Specific inhibition of the BimBH3-Bcl2A1 protein–protein interaction ...was obtained in vitro and in cancer cells by shortening the peptide to 14 residues, inserting two cyclization constraints to stabilize a water-stable α-helix, and incorporating an N-terminal acrylamide electrophile for selective covalent bonding to Bcl2A1. Mass spectrometry of trypsin-digested bands on electrophoresis gels established covalent bonding of an electrophilic helix to just one of the three cysteines in Bcl2A1, the one (Cys55) at the BimBH3-Bcl2A1 protein–protein interaction interface. Optimizing the helix-inducing constraints and the sequence subsequently enabled electrophile removal without loss of inhibitor potency. The bicyclic helical peptides were potent, cell permeable, plasma-stable, dual inhibitors of Bcl2A1 and Mcl-1 with high selectivity over other Bcl2 proteins. One bicyclic peptide was shown to inhibit the interaction between a pro-apoptotic protein (Bim) and either endogenous Bcl2A1 or Mcl-1, to induce apoptosis of SKMel28 human melanoma cells, and to sensitize them for enhanced cell death by the anticancer drug etoposide. These approaches look promising for chemically silencing intracellular proteins.
Human interleukin (IL) 1 receptor-associated kinase 4 (IRAK-4) deficiency is a recently discovered primary immunodeficiency that impairs Toll/IL-1R immunity, except for the Toll-like receptor (TLR) ...3- and TLR4-interferon (IFN)-alpha/beta pathways. The clinical and immunological phenotype remains largely unknown. We diagnosed up to 28 patients with IRAK-4 deficiency, tested blood TLR responses for individual leukocyte subsets, and TLR responses for multiple cytokines. The patients' peripheral blood mononuclear cells (PBMCs) did not induce the 11 non-IFN cytokines tested upon activation with TLR agonists other than the nonspecific TLR3 agonist poly(I:C). The patients' individual cell subsets from both myeloid (granulocytes, monocytes, monocyte-derived dendritic cells MDDCs, myeloid DCs MDCs, and plasmacytoid DCs) and lymphoid (B, T, and NK cells) lineages did not respond to the TLR agonists that stimulated control cells, with the exception of residual responses to poly(I:C) and lipopolysaccharide in MDCs and MDDCs. Most patients (22 out of 28; 79%) suffered from invasive pneumococcal disease, which was often recurrent (13 out of 22; 59%). Other infections were rare, with the exception of severe staphylococcal disease (9 out of 28; 32%). Almost half of the patients died (12 out of 28; 43%). No death and no invasive infection occurred in patients older than 8 and 14 yr, respectively. The IRAK-4-dependent TLRs and IL-1Rs are therefore vital for childhood immunity to pyogenic bacteria, particularly Streptococcus pneumoniae. Conversely, IRAK-4-dependent human TLRs appear to play a redundant role in protective immunity to most infections, at most limited to childhood immunity to some pyogenic bacteria.
Over the last few years many articles have been published in an attempt to provide performance benchmarks for virtual screening tools. While this research has imparted useful insights, the myriad ...variables controlling said studies place significant limits on results interpretability. Here we investigate the effects of these variables, including analysis of calculation setup variation, the effect of target choice, active/decoy set selection (with particular emphasis on the effect of analogue bias) and enrichment data interpretation. In addition the optimization of the publicly available DUD benchmark sets through analogue bias removal is discussed, as is their augmentation through the addition of large diverse data sets collated using WOMBAT.
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Group A Streptococcus (GAS) is a highly-adapted and human-restricted pathogen responsible for a high global burden of disease across a diverse clinical spectrum. Vaccine development ...has been impeded by scientific, regulatory, and commercial obstacles. Human infection studies (HIS) are increasingly contributing to drug, diagnostics, and vaccine development, reducing uncertainty at early stages, especially for pathogens with animal models that incompletely reproduce key elements of human disease. We review the small number of historical GAS HIS and present the study protocol for a dose-ranging inpatient study in healthy adults. The primary objective of the study is to establish a new GAS pharyngitis HIS with an attack rate of at least 60% as a safe and reliable platform for vaccine evaluation and pathogenesis research. According to an adaptive dose-ranging study design, emm75 GAS doses manufactured in keeping with principles of Good Manufacturing Practice will be directly applied by swab to the pharynx of carefully screened healthy adult volunteers at low risk of severe complicated GAS disease. Participants will remain as closely monitored inpatients for up to six days, observed for development of the primary outcome of acute symptomatic pharyngitis, as defined by clinical and microbiological criteria. All participants will be treated with antibiotics and followed as outpatients for six months. An intensive sampling schedule will facilitate extensive studies of host and organism dynamics during experimental pharyngitis. Ethics approval has been obtained and the study has been registered at ClinicalTrials.gov (NCT03361163).
The biological role played by non-BET bromodomains remains poorly understood, and it is therefore imperative to identify potent and highly selective inhibitors to effectively explore the biology of ...individual bromodomain proteins. A ligand-efficient nonselective bromodomain inhibitor was identified from a 6-methyl pyrrolopyridone fragment. Small hydrophobic substituents replacing the N-methyl group were designed directing toward the conserved bromodomain water pocket, and two distinct binding conformations were then observed. The substituents either directly displaced and rearranged the conserved solvent network, as in BRD4(1) and TAF1(2), or induced a narrow hydrophobic channel adjacent to the lipophilic shelf, as in BRD9 and CECR2. The preference of distinct substituents for individual bromodomains provided selectivity handles useful for future lead optimization efforts for selective BRD9, CECR2, and TAF1(2) inhibitors.
Autosomal recessive interleukin-1 receptor-associated kinase (IRAK)-4 and myeloid differentiation factor (MyD)88 deficiencies impair Toll-like receptor (TLR)- and interleukin-1 receptor-mediated ...immunity. We documented the clinical features and outcome of 48 patients with IRAK-4 deficiency and 12 patients with MyD88 deficiency, from 37 kindreds in 15 countries.The clinical features of IRAK-4 and MyD88 deficiency were indistinguishable. There were no severe viral, parasitic, and fungal diseases, and the range of bacterial infections was narrow. Noninvasive bacterial infections occurred in 52 patients, with a high incidence of infections of the upper respiratory tract and the skin, mostly caused by Pseudomonas aeruginosa and Staphylococcus aureus, respectively. The leading threat was invasive pneumococcal disease, documented in 41 patients (68%) and causing 72 documented invasive infections (52.2%). P. aeruginosa and Staph. aureus documented invasive infections also occurred (16.7% and 16%, respectively, in 13 and 13 patients, respectively). Systemic signs of inflammation were usually weak or delayed. The first invasive infection occurred before the age of 2 years in 53 (88.3%) and in the neonatal period in 19 (32.7%) patients. Multiple or recurrent invasive infections were observed in most survivors (n = 36/50, 72%).Clinical outcome was poor, with 24 deaths, in 10 cases during the first invasive episode and in 16 cases of invasive pneumococcal disease. However, no death and invasive infectious disease were reported in patients after the age of 8 years and 14 years, respectively. Antibiotic prophylaxis (n = 34), antipneumococcal vaccination (n = 31), and/or IgG infusion (n = 19), when instituted, had a beneficial impact on patients until the teenage years, with no seemingly detectable impact thereafter.IRAK-4 and MyD88 deficiencies predispose patients to recurrent life-threatening bacterial diseases, such as invasive pneumococcal disease in particular, in infancy and early childhood, with weak signs of inflammation. Patients and families should be informed of the risk of developing life-threatening infections; empiric antibacterial treatment and immediate medical consultation are strongly recommended in cases of suspected infection or moderate fever. Prophylactic measures in childhood are beneficial, until spontaneous improvement occurs in adolescence.
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