Small-Molecule Inhibition of the Acyl-Lysine Reader ENL as a Strategy against Acute Myeloid Leukemia.

Unlabelled: The chromatin reader eleven-nineteen leukemia (ENL) has been identified as a critical dependency in acute myeloid leukemia (AML), but its therapeutic potential remains unclear. We describe a potent and orally bioavailable small-molecule inhibitor of ENL, TDI-11055, which displaces ENL from chromatin by blocking its YEATS domain interaction with acylated histones. Cell lines and primary patient samples carrying MLL rearrangements or NPM1 mutations are responsive to TDI-11055.

A Chemical Strategy toward Novel Brain-Penetrant EZH2 Inhibitors.

Aberrant gene-silencing through dysregulation of polycomb protein activity has emerged as an important oncogenic mechanism in cancer, implicating polycomb proteins as important therapeutic targets. Recently, an inhibitor targeting EZH2, the methyltransferase component of PRC2, received U.S.

Water fluoridation, dental caries and parental ratings of child oral health.

Objectives: Previous studies have identified many demographic, socioeconomic, behavioural and clinical variables associated with subjective parental ratings of child oral health. This study investigated associations between children's lifetime exposure to fluoridated drinking water (LEFW) and dental caries prevalence and parental ratings.

Methods: Australia's National Child Oral Health Study 2012-2014 conducted oral epidemiological examinations for 24 664 children aged 5-14 and investigated risk factors for child oral health and disease through questionnaires.

Discovery of TDI-10229: A Potent and Orally Bioavailable Inhibitor of Soluble Adenylyl Cyclase (sAC, ADCY10).

Soluble adenylyl cyclase (sAC) has gained attention as a potential therapeutic target given the role of this enzyme in intracellular signaling. We describe successful efforts to design improved sAC inhibitors amenable for interrogation of sAC inhibition to assess its potential therapeutic applications. This work culminated in the identification of TDI-10229 (), which displays nanomolar inhibition of sAC in both biochemical and cellular assays and exhibits mouse pharmacokinetic properties sufficient to warrant its use as an tool compound.

Novel Pure αVβ3 Integrin Antagonists That Do Not Induce Receptor Extension, Prime the Receptor, or Enhance Angiogenesis at Low Concentrations.

The integrin αVβ3 receptor has been implicated in several important diseases, but no antagonists are approved for human therapy. One possible limitation of current small-molecule antagonists is their ability to induce a major conformational change in the receptor that induces it to adopt a high-affinity ligand-binding state. In response, we used structural inferences from a pure peptide antagonist to design the small-molecule pure antagonists TDI-4161 and TDI-3761.

Public Dental Services, Queensland, Australia: Charles Octavius Vidgen.

Charles Octavius Vidgen was the Superintendent of the Brisbane Dental Hospital, c1917-1945. Hitherto, commentators' reviews rely on imposing but narrow streams of evidence to either ignore Vidgen's influence on the dental profession or portray it as both peripheral and controversial. In this account, the authors use historical method to provide a revisionist account of Vidgen's professional profile and, to a lesser extent, a character resurrection.

Public Dental Services, Queensland: Alan Thomas Robertson.

Alan Thomas Robertson's career as Assistant Superintendent Brisbane Dental Hospital [1927-1945] and Acting Superintendent [1945-1946] spanned difficult times. In Victoria, against a backdrop of family tragedy and World War I, Robertson achieved distinguished academic and war-service records. Following the move to Queensland, Robertson either experienced or witnessed the Great Depression, World War II and affiliated paradigm shifts in government policy, dental education and the system of the delivery of dental services.

Brisbane Dental Hospital and Queensland University Dental College Building Alias : Heritage Listing.

The National Trust of Queensland placed the Brisbane Dental Hospital and Queensland College of Dentistry Building, alias , on the National Trust of Queensland Register in April 1997. This action generated no statutory consequences. Within days, the trust nominated for listing on the Queensland Heritage Register.

Antimalarial proteasome inhibitor reveals collateral sensitivity from intersubunit interactions and fitness cost of resistance.

We describe noncovalent, reversible asparagine ethylenediamine (AsnEDA) inhibitors of the proteasome (Pf20S) β5 subunit that spare all active subunits of human constitutive and immuno-proteasomes. The compounds are active against erythrocytic, sexual, and liver-stage parasites, against parasites resistant to current antimalarials, and against strains from patients in Africa. The β5 inhibitors synergize with a β2 inhibitor in vitro and in mice and with artemisinin.

Public Dental Services, Queensland: Alfred James Hoole.

Historians have given limited attention to the genesis and evolution of public dental services across Queensland. The Secretary [Minister] for Home Affairs and later Premier, Edward 'Ned' Hanlon, was the political architect of accessible public hospital and dental facilities. However it was administrator and dentist, Alfred James Hoole, who orchestrated the practical details in the field.

Aminopyrimidine Class Aggregation Inhibitor Effectively Blocks Aβ-Fibrinogen Interaction and Aβ-Induced Contact System Activation.

Accumulating evidence suggests that fibrinogen, a key protein in the coagulation cascade, plays an important role in circulatory dysfunction in Alzheimer's disease (AD). Previous work has shown that the interaction between fibrinogen and β-amyloid (Aβ), a hallmark pathological protein in AD, induces plasmin-resistant abnormal blood clots, delays fibrinolysis, increases inflammation, and aggravates cognitive function in mouse models of AD. Since Aβ oligomers have a much stronger affinity for fibrinogen than Aβ monomers, we tested whether amyloid aggregation inhibitors could block the Aβ-fibrinogen interaction and found that some Aβ aggregation inhibitors showed moderate inhibitory efficacy against this interaction.

Public Dental Services, Queensland: Edward "Ned" Michael Hanlon.

Within the Australian context, commentators often portray the Queensland system of delivery of public dental services as state-specific. A poorly explored dimension within this narrative is the contribution from Ned Hanlon. The authors use historical methods to address this inadequacy in the literature.

The Medicare Chronic Disease Dental Scheme: Historical, Scientific, Socio-political Origins.

While evidence and expert opinion are the foundations of effective policy, the politics, economics, and timing of a proposal can affect outcome. Australian government involvement in the planning, funding and delivery of dental services has been minimal and inconsistent. Many believe that the hybrid dispersal model of shared constitutional power has intermittently led to poor administration of national health policy.

Chemical structure-guided design of dynapyrazoles, cell-permeable dynein inhibitors with a unique mode of action.

Cytoplasmic dyneins are motor proteins in the AAA+ superfamily that transport cellular cargos toward microtubule minus-ends. Recently, ciliobrevins were reported as selective cell-permeable inhibitors of cytoplasmic dyneins. As is often true for first-in-class inhibitors, the use of ciliobrevins has in part been limited by low potency.

Identification of Highly Specific Diversity-Oriented Synthesis-Derived Inhibitors of Clostridium difficile.

In 2013, the Centers for Disease Control highlighted Clostridium difficile as an urgent threat for antibiotic-resistant infections, in part due to the emergence of highly virulent fluoroquinolone-resistant strains. Limited therapeutic options currently exist, many of which result in disease relapse. We sought to identify molecules specifically targeting C.

Structural and conformational determinants of macrocycle cell permeability.

Macrocycles are of increasing interest as chemical probes and drugs for intractable targets like protein-protein interactions, but the determinants of their cell permeability and oral absorption are poorly understood. To enable rational design of cell-permeable macrocycles, we generated an extensive data set under consistent experimental conditions for more than 200 non-peptidic, de novo-designed macrocycles from the Broad Institute's diversity-oriented screening collection. This revealed how specific functional groups, substituents and molecular properties impact cell permeability.

Diversity-oriented synthesis yields novel multistage antimalarial inhibitors.

Antimalarial drugs have thus far been chiefly derived from two sources-natural products and synthetic drug-like compounds. Here we investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of synthetic compounds that have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections. We report the identification of such compounds with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase.

Novel diversity-oriented synthesis-derived respiratory syncytial virus inhibitors identified via a high throughput replicon-based screen.

Respiratory syncytial virus (RSV) infections affect millions of children and adults every year. Despite the significant disease burden, there are currently no safe and effective vaccines or therapeutics. We employed a replicon-based high throughput screen combined with live-virus triaging assays to identify three novel diversity-oriented synthesis-derived scaffolds with activity against RSV.

High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines.

Hundreds of genetically characterized cell lines are available for the discovery of genotype-specific cancer vulnerabilities. However, screening large numbers of compounds against large numbers of cell lines is currently impractical, and such experiments are often difficult to control. Here we report a method called PRISM that allows pooled screening of mixtures of cancer cell lines by labeling each cell line with 24-nucleotide barcodes.

Advancing Biological Understanding and Therapeutics Discovery with Small-Molecule Probes.

Small-molecule probes can illuminate biological processes and aid in the assessment of emerging therapeutic targets by perturbing biological systems in a manner distinct from other experimental approaches. Despite the tremendous promise of chemical tools for investigating biology and disease, small-molecule probes were unavailable for most targets and pathways as recently as a decade ago. In 2005, the NIH launched the decade-long Molecular Libraries Program with the intent of innovating in and broadening access to small-molecule science.

The Brisbane Dental Hospital Building: "The Palace" An Era Ends.

Constitutional, educational, humanitarian and political considerations underpinned the design and construction of the Brisbane Dental Hospital Building, often colloquially referred to as "The Palace." The Queensland Heritage Council's listing of the Brisbane Dental Hospital Building on The Queensland Heritage Register in 1999 confirms the cultural significance of Nowland's architectural signature, the historical importance of the Wickham Park precinct and prior students' connection with the building. Influences on decisions determining the location, grand design and timing of construction of the Brisbane Dental Hospital Building emanated from a far bigger and largely unrecorded political picture.

Diagnosis and management of a maxillary lateral incisor exhibiting dens invaginatus and dens evaginatus.

This case report, involving an indigenous Australian, presents the diagnosis and non-surgical endodontic management of a 22 with developmental abnormalities. They include a dens evaginatus and a dens invaginatus that extends to an apical burst in a second truncated root. Cone-beam computed tomography and endodontic microscopy were not available to the clinician.

Synthesis of stereochemically and skeletally diverse fused ring systems from functionalized C-glycosides.

A diversity-oriented synthesis (DOS) strategy was developed for the synthesis of stereochemically diverse fused-ring systems containing a pyran moiety. Each scaffold contains an amine and methyl ester for further diversification via amine capping and amide coupling. Scaffold diversity was evaluated in comparison to previously prepared scaffolds by a shape-based principal moments of inertia (PMI) analysis.