Discovery of Reversible Covalent Bruton's Tyrosine Kinase Inhibitors PRN473 and PRN1008 (Rilzabrutinib).

Bruton's tyrosine kinase (BTK), a Tec family tyrosine kinase, is critical in immune pathways as an essential intracellular signaling element, participating in both adaptive and immune responses. Currently approved BTK inhibitors are irreversible covalent inhibitors and limited to oncology indications. Herein, we describe the design of covalent reversible BTK inhibitors and the discoveries of PRN473 () and rilzabrutinib (PRN1008, ).

Preclinical Efficacy and Anti-Inflammatory Mechanisms of Action of the Bruton Tyrosine Kinase Inhibitor Rilzabrutinib for Immune-Mediated Disease.

Bruton tyrosine kinase (BTK) is expressed in B cells and innate immune cells, acting as an essential signaling element in multiple immune cell pathways. Selective BTK inhibition has the potential to target multiple immune-mediated disease pathways. Rilzabrutinib is an oral, reversible, covalent BTK inhibitor designed for immune-mediated diseases.

Data Linkage: Canadian and Australian Perspectives on a Valuable Methodology for Intellectual and Developmental Disability Research.

Data linkage holds great promise for generating new information about people with intellectual and developmental disabilities (IDD) as a population, yet few centers have developed the infrastructure to utilize this methodology. Two examples, from Canada and Australia, describe their efforts in building data linkage capabilities, and how linked databases can be used to identify persons with IDD and used for population-based research. The value of data linkage is illustrated through new estimates of prevalence of IDD; health service utilization patterns; associations with sociodemographic characteristics, and with physical and mental health conditions (e.

The Proteome-Wide Potential for Reversible Covalency at Cysteine.

Reversible covalency, achieved with, for instance, highly electron-deficient olefins, offers a compelling strategy to design chemical probes and drugs that benefit from the sustained target engagement afforded by irreversible compounds, while avoiding permanent protein modification. Reversible covalency has mainly been evaluated for cysteine residues in individual kinases and the broader potential for this strategy to engage cysteines across the proteome remains unexplored. Herein, we describe a mass-spectrometry-based platform that integrates gel filtration with activity-based protein profiling to assess cysteine residues across the human proteome for both irreversible and reversible interactions with small-molecule electrophiles.

Impact of first and second eye cataract surgery on physical activity: a prospective study.

Objectives: To investigate the impact of first eye and second eye cataract surgery on the level of physical activity undertaken by older adults with bilateral cataract.

Design: Prospective cohort study.

Setting: Three public ophthalmology clinics in Western Australia.

Morbidity burden and community-based palliative care are associated with rates of hospital use by people with schizophrenia in the last year of life: A population-based matched cohort study.

Objective: People with schizophrenia face an increased risk of premature death from chronic diseases and injury. This study describes the trajectory of acute care health service use in the last year of life for people with schizophrenia and how this varied with receipt of community-based specialist palliative care and morbidity burden.

Method: A population-based retrospective matched cohort study of people who died from 01/01/2009 to 31/12/2013 with and without schizophrenia in Western Australia.

The impact of first- and second-eye cataract surgery on motor vehicle crashes and associated costs.

Objective: to evaluate the association between first- and second-eye cataract surgery and motor vehicle crashes for older drivers and the associated costs to the community.

Design: retrospective population-based cohort study.

Subjects: a total of 2,849 drivers aged 60 years and older who had undergone both first- and second-eye cataract surgery were involved in 3,113 motor vehicle crashes as drivers during the study period.

The impact of first and second eye cataract surgeries on falls: a prospective cohort study.

Purpose: The purpose of this study was to investigate the impact of the first and second eye cataract surgeries on the risk of falls in participants with bilateral cataract and to determine which changes in visual measures are associated with changes in the number of falls throughout the cataract surgery process.

Patients And Methods: Fifty-five older adults with bilateral cataract aged 55+ years were assessed at three time points during the cataract surgery process, and they completed a falls diary. Two separate generalized estimating equation-negative binomial models were undertaken to assess changes in the number of falls before first eye cataract surgery, between first and second eye surgeries, and after second eye cataract surgery and which changes in visual measures were associated with changes in the number of falls.

Use of health services in the last year of life and cause of death in people with intellectual disability: a retrospective matched cohort study.

Objective: To describe the cause of death together with emergency department presentations and hospital admissions in the last year of life of people with intellectual disability.

Method: A retrospective matched cohort study using de-identified linked data of people aged 20 years or over, with and without intellectual disability who died during 2009 to 2013 in Western Australia. Emergency department presentations and hospital admissions in the last year of life of people with intellectual disability are described along with cause of death.

The Irreversible Covalent Fibroblast Growth Factor Receptor Inhibitor PRN1371 Exhibits Sustained Inhibition of FGFR after Drug Clearance.

An increasing number of cancers are known to harbor mutations, translocations, or amplifications in the fibroblast growth factor receptor (FGFR) family of kinases. The FGFR inhibitors evaluated in clinical trials to date have shown promise at treating these cancers. Here, we describe PRN1371, an irreversible covalent inhibitor of FGFR1-4 targeting a cysteine within the kinase active site.

Discovery of the Irreversible Covalent FGFR Inhibitor 8-(3-(4-Acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (PRN1371) for the Treatment of Solid Tumors.

Aberrant signaling of the FGF/FGFR pathway occurs frequently in cancers and is an oncogenic driver in many solid tumors. Clinical validation of FGFR as a therapeutic target has been demonstrated in bladder, liver, lung, breast, and gastric cancers. Our goal was to develop an irreversible covalent inhibitor of FGFR1-4 for use in oncology indications.

Psychotropic Medication and Substance Use during Pregnancy by Women with Severe Mental Illness.

Background: Sociodemographic factors, alcohol and drug intake, and maternal health are known to be associated with adverse outcomes in pregnancy for women with severe mental illness in addition to their use of psychotropic medication. In this study, we describe the demographic characteristics of women hospitalized for severe mental illness along with their use of medication and other drugs during the pregnancy period.

Methods: A clinical case note review of women with psychosis who were hospitalized at the State Psychiatric Hospital in Western Australia during 1966-1996, gave birth between 1980 and 1992, and received psychiatric treatment during the pregnancy period.

Issues using linkage of hospital records and death certificate data to determine the size of a potential palliative care population.

Background: Studies aiming to identify palliative care populations have used data from death certificates and in some cases hospital records. The size and characteristics of the identified populations can show considerable variation depending on the data sources used. It is important that service planners and researchers are aware of this.

The collective impact of rare diseases in Western Australia: an estimate using a population-based cohort.

Purpose: It has been argued that rare diseases should be recognized as a public health priority. However, there is a shortage of epidemiological data describing the true burden of rare diseases. This study investigated hospital service use to provide a better understanding of the collective health and economic impacts of rare diseases.

Prolonged and tunable residence time using reversible covalent kinase inhibitors.

Drugs with prolonged on-target residence times often show superior efficacy, yet general strategies for optimizing drug-target residence time are lacking. Here we made progress toward this elusive goal by targeting a noncatalytic cysteine in Bruton's tyrosine kinase (BTK) with reversible covalent inhibitors. Using an inverted orientation of the cysteine-reactive cyanoacrylamide electrophile, we identified potent and selective BTK inhibitors that demonstrated biochemical residence times spanning from minutes to 7 d.

Targeting interleukin-2-inducible T-cell kinase (ITK) and resting lymphocyte kinase (RLK) using a novel covalent inhibitor PRN694.

Interleukin-2-inducible T-cell kinase (ITK) and resting lymphocyte kinase (RLK or TXK) are essential mediators of intracellular signaling in both normal and neoplastic T-cells and natural killer (NK) cells. Thus, ITK and RLK inhibitors have therapeutic potential in a number of human autoimmune, inflammatory, and malignant diseases. Here we describe a novel ITK/RLK inhibitor, PRN694, which covalently binds to cysteine residues 442 of ITK and 350 of RLK and blocks kinase activity.

Characterization of RO5126946, a Novel α7 nicotinic acetylcholine receptor-positive allosteric modulator.

Both preclinical evidence and clinical evidence suggest that α7 nicotinic acetylcholine receptor activation (α7nAChR) improves cognitive function, the decline of which is associated with conditions such as Alzheimer's disease and schizophrenia. Moreover, allosteric modulation of α7nAChR is an emerging therapeutic strategy in an attempt to avoid the rapid desensitization properties associated with the α7nAChR after orthosteric activation. We used a calcium assay to screen for positive allosteric modulators (PAMs) of α7nAChR and report on the pharmacologic characterization of the novel compound RO5126946 (5-chloro-N-[(1S,3R)-2,2-dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2-methoxy-benzamide), which allosterically modulates α7nAChR activity.

The Western Australian family connections genealogical project: detection of familial occurrences of single gene and chromosomal disorders.

Aim: To investigate using a Western Australian (WA) genealogical database for the identification of single gene and chromosome disorders among families.

Method: Hospital admissions for single gene and chromosome disorders recorded during 2000-2006 were identified from the WA Hospital Morbidity Data System. The proportion of these conditions occurring in family groups was then identified using genealogical links created through the WA Family Connections Genealogical Project.

Discovery of N-[4-[6-tert-butyl-5-methoxy-8-(6-methoxy-2-oxo-1H-pyridin-3-yl)-3-quinolyl]phenyl]methanesulfonamide (RG7109), a potent inhibitor of the hepatitis C virus NS5B polymerase.

In the past few years, there have been many advances in the efforts to cure patients with hepatitis C virus (HCV). The ultimate goal of these efforts is to develop a combination therapy consisting of only direct-antiviral agents (DAAs). In this paper, we discuss our efforts that led to the identification of a bicyclic template with potent activity against the NS5B polymerase, a critical enzyme on the life cycle of HCV.

Discovery of a novel series of potent non-nucleoside inhibitors of hepatitis C virus NS5B.

Hepatitis C virus (HCV) is a major global public health problem. While the current standard of care, a direct-acting antiviral (DAA) protease inhibitor taken in combination with pegylated interferon and ribavirin, represents a major advancement in recent years, an unmet medical need still exists for treatment modalities that improve upon both efficacy and tolerability. Toward those ends, much effort has continued to focus on the discovery of new DAAs, with the ultimate goal to provide interferon-free combinations.

De novo fragment design: a medicinal chemistry approach to fragment-based lead generation.

The use of fragments with low binding affinity for their targets as starting points has received much attention recently. Screening of fragment libraries has been the most common method to find attractive starting points. Herein, we describe a unique, alternative approach to generating fragment leads.

Baseline investigations of folate status in Aboriginal and non-Aboriginal West Australians prior to the introduction of mandatory fortification.

Objective: In September 2009, Australia implemented mandatory folic acid fortification of wheat flour for bread-making to reduce the incidence of neural tube defects. Our study aimed to establish baseline folate status data in Aboriginal and non-Aboriginal Western Australians.

Methods: Patients who presented at a health service or collection centre for blood tests were invited to participate.

3-heterocyclyl quinolone inhibitors of the HCV NS5B polymerase.

The discovery and optimization of a novel class of quinolone small-molecules that inhibit NS5B polymerase, a key enzyme of the HCV viral life-cycle, is described. Our research led to the replacement of a hydrolytically labile ester functionality with bio-isosteric heterocycles. An X-ray crystal structure of a key analog bound to NS5B facilitated the optimization of this series of compounds to afford increased activity against the target enzyme and in the cell-based replicon assay system.

The impact of single gene and chromosomal disorders on hospital admissions in an adult population.

Although the role of single gene and chromosomal disorders in pediatric illness has been recognized since the 1970s, there are few data describing the impact of these often severe disorders on the health of the adult population. In this study, we present population data describing the impact of single gene and chromosomal disorders on hospital admissions of patients aged 20 years and over in Western Australia between 2000 and 2006. The number, length, and cost of admissions were investigated and compared between disease categories and age groups and to hospital admissions for any reason.

Compliance with professional guidelines with reference to familial cancer services.

Objective: Professional guidelines define the risk categorisation of patients for a genetic predisposition to cancer based on family history. These guidelines inform the appropriate referral of patients to specialist familial cancer services. Our study aimed to determine the quality of referral letters from general practitioners and specialists to genetic services for breast, ovarian and colorectal cancers, and their compliance with relevant professional guidelines.