Meaningful co-production to bring meaningful change: Developing the Allied Health Professionals Dementia Framework for Wales together.

In line with increasing participatory approaches to service and research design, there is a growing appreciation of the need to understand the lived experience of people accessing care and support, including people living with dementia, their carers and supporters. This article describes the process and value of co-production, used alongside principles of appreciative inquiry and evidence-informed practice, as an approach to developing a strategic workforce framework, aimed at increasing access to Allied Health Professionals (AHPs) for people living with dementia and their carers. Engaging in the co-production approach throughout the project lifecycle resulted in positive outcomes as reported by people with lived experience and professionals who were involved, as well as a published national framework that is rooted in the first-hand experiences of people living with dementia, their carers and supporters.

Fragment-Based Discovery of Allosteric Inhibitors of SH2 Domain-Containing Protein Tyrosine Phosphatase-2 (SHP2).

The ubiquitously expressed protein tyrosine phosphatase SHP2 is required for signaling downstream of receptor tyrosine kinases (RTKs) and plays a role in regulating many cellular processes. Genetic knockdown and pharmacological inhibition of SHP2 suppresses RAS/MAPK signaling and inhibit the proliferation of RTK-driven cancer cell lines. Here, we describe the first reported fragment-to-lead campaign against SHP2, where X-ray crystallography and biophysical techniques were used to identify fragments binding to multiple sites on SHP2. Structure-guided optimization, including several computational methods, led to the discovery of two structurally distinct series of SHP2 inhibitors binding to the previously reported allosteric tunnel binding site (Tunnel Site). One of these series was advanced to a low-nanomolar lead that inhibited tumor growth when dosed orally to mice bearing HCC827 xenografts. Furthermore, a third series of SHP2 inhibitors was discovered binding to a previously unreported site, lying at the interface of the C-terminal SH2 and catalytic domains.

Fragment-to-Lead Medicinal Chemistry Publications in 2022.

This Perspective is the eighth in an annual series that summarizes successful fragment-to-lead (F2L) case studies published each year. A tabulated summary of relevant articles published in 2022 is provided, and features such as target class, screening methods, and ligand efficiency are discussed both for the 2022 examples and for the combined examples over the years 2015-2022. In addition, trends and new developments in the field are summarized. In 2022, 18 publications described successful fragment-to-lead studies, including the development of three clinical compounds (MTRX1719, MK-8189, and BI-823911).

Fragment-to-Lead Medicinal Chemistry Publications in 2021.

This Perspective is the seventh in an annual series that summarizes successful Fragment-to-Lead (F2L) case studies published in a given year. A tabulated summary of relevant articles published in 2021 is provided, and features such as target class, screening methods, and ligand efficiency are discussed, both for the 2021 examples and for the combined examples over the years 2015-2021. In addition, trends and new developments in the field are summarized. In particular, the use of structural information in fragment-based drug discovery is discussed.

Masseter muscle rigidity and the role of DNA analysis to confirm malignant hyperthermia susceptibility.

Malignant hyperthermia (MH) is an uncommon, autosomal dominant disorder of skeletal muscle, triggered by inhalational anaesthetics or depolarizing muscle relaxants. Masseter muscle rigidity (MMR) can be regarded as potentially a preceding sign for an MH reaction. Susceptibility to MH can be determined by the in vitro contracture test (IVCT) or DNA analysis where a familial variant is known. Our aims were to review patients with MMR, where IVCT and DNA analysis had been undertaken, to determine if DNA analysis could be used as an initial screening tool for MH susceptibility, and, by reviewing standard monitored variables (SMVs), to determine if any clinical characteristics could be used to differentiate between MMR patients who are MH susceptible (MHS) and those who are not. Patients with MMR were identified from the Palmerston North Hospital MH Reactions Database. IVCT and DNA analysis results were documented. DNA testing was performed retrospectively in the majority of patients as many patients had presented before DNA analysis was available. Forty-one patients were analysed. Fourteen were DNA positive/IVCT positive and six DNA positive only (48% in total), seven were IVCT positive/DNA negative and 14 were IVCT normal. Increased creatine kinase (>18,000 units/L) was consistent with MH susceptibility. Severity of MMR was not linked to MH susceptibility. This study confirmed that DNA analysis can be used as a first-line test for MH susceptibility in patients presenting with MMR (consistent with European MH Group recommendations). Creatine kinase was the only SMV that was significantly different between MHS and MH normal individuals.

Relationship Between Diabetic Variables and Outcomes After Coronary Artery Bypass Grafting in Diabetic Patients.

BACKGROUND: Nearly half of the patients undergoing coronary artery bypass grafting (CABG) have diabetes. There is mixed data as to whether preoperative (haemoglobin A1c{HbA1c}) and/or perioperative diabetes control is associated with mortality and morbidity after CABG. We reviewed the characteristics and outcomes of diabetic patients undergoing CABG with a focus on HbA1c, perioperative glucose levels and diabetic treatment regimens. METHODS: Diabetic patients undergoing CABG during July 2010 to June 2012 were studied (n=306). The last preoperative HbA1c levels, and perioperative glucose levels (mean and coefficient of variation {CV}) were retrospectively recorded, as well as the pre-existing and perioperative diabetes treatment regimens for analyses. RESULTS: Mean HbA1c was 7.7+/-1.6%, and 11.1% (34), 56.2% (172), and 32.7% (100) of patients were managed preoperatively with diet only, oral diabetic medications and insulin respectively. For operative mortality which occurred in 2.0%, C-statistics (95% confidence interval) was only significant for HbA1c, 0.855 (0.757-0.975), and glucose CV on the day of surgery, 0.722 (0.567-0.877). HbA1c also detected postoperative renal failure, C-statistic 0.617 (0.504-0.730), but not other complications or mortality during follow-up. In multivariate analysis, HbA1c was the only diabetes-related independent predictor of operative mortality, hazards ratio 4.13 (1.04-16.4), and none of the diabetes-related variables predicted mortality during follow-up or other postoperative complications. CONCLUSION: Preoperative HbA1c was the only diabetic variable to independently predict operative mortality after CABG, suggesting medium-term preoperative diabetes control is more important and prognostic of operative outcomes than perioperative diabetes control.

Discovery of an allosteric mechanism for the regulation of HCV NS3 protein function.

Here we report a highly conserved new binding site located at the interface between the protease and helicase domains of the hepatitis C virus (HCV) NS3 protein. Using a chemical lead, identified by fragment screening and structure-guided design, we demonstrate that this site has a regulatory function on the protease activity via an allosteric mechanism. We propose that compounds binding at this allosteric site inhibit the function of the NS3 protein by stabilizing an inactive conformation and thus represent a new class of direct-acting antiviral agents.

Fragment-based drug discovery applied to Hsp90. Discovery of two lead series with high ligand efficiency.

Inhibitors of the chaperone Hsp90 are potentially useful as chemotherapeutic agents in cancer. This paper describes an application of fragment screening to Hsp90 using a combination of NMR and high throughput X-ray crystallography. The screening identified an aminopyrimidine with affinity in the high micromolar range and subsequent structure-based design allowed its optimization into a low nanomolar series with good ligand efficiency. A phenolic chemotype was also identified in fragment screening and was found to bind with affinity close to 1 mM. This fragment was optimized using structure based design into a resorcinol lead which has subnanomolar affinity for Hsp90, excellent cell potency, and good ligand efficiency. This fragment to lead campaign improved affinity for Hsp90 by over 1,000,000-fold with the addition of only six heavy atoms. The companion paper (DOI: 10.1021/jm100060b) describes how the resorcinol lead was optimized into a compound that is now in clinical trials for the treatment of cancer.

Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design.

Inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) are currently generating significant interest in clinical development as potential treatments for cancer. In a preceding publication (DOI: 10.1021/jm100059d ) we describe Astex's approach to screening fragments against Hsp90 and the subsequent optimization of two hits into leads with inhibitory activities in the low nanomolar range. This paper describes the structure guided optimization of the 2,4-dihydroxybenzamide lead molecule 1 and details some of the drug discovery strategies employed in the identification of AT13387 (35), which has progressed through preclinical development and is currently being tested in man.

From fragment to clinical candidate--a historical perspective.

As recently as ten years ago few scientists had heard of fragment screening, let alone considered low molecular weight fragments (MW <300) with weak binding affinities to be attractive start points for drug discovery programmes. Today, however, there is widespread acceptance that these fragments can be progressed into lead series and on to become clinical candidates. Consequently, over the past three to four years, fragment-based drug discovery has become firmly established within the biotechnology and pharmaceutical industries as a complimentary strategy to high-throughput screening. In this review, we give a historical perspective of how rapidly fragment-based drug discovery has developed and describe a number of clinical compounds discovered using this approach.

Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design.

The application of fragment-based screening techniques to cyclin dependent kinase 2 (CDK2) identified multiple (>30) efficient, synthetically tractable small molecule hits for further optimization. Structure-based design approaches led to the identification of multiple lead series, which retained the key interactions of the initial binding fragments and additionally explored other areas of the ATP binding site. The majority of this paper details the structure-guided optimization of indazole (6) using information gained from multiple ligand-CDK2 cocrystal structures. Identification of key binding features for this class of compounds resulted in a series of molecules with low nM affinity for CDK2. Optimisation of cellular activity and characterization of pharmacokinetic properties led to the identification of 33 (AT7519), which is currently being evaluated in clinical trials for the treatment of human cancers.

Identification of novel p38alpha MAP kinase inhibitors using fragment-based lead generation.

We describe the structure-guided optimization of the molecular fragments 2-amino-3-benzyloxypyridine 1 (IC(50) 1.3 mM) and 3-(2-(4-pyridyl)ethyl)indole 2 (IC(50) 35 microM) identified using X-ray crystallographic screening of p38alpha MAP kinase. Using two separate case studies, the article focuses on the key compounds synthesized, the structure-activity relationships and the binding mode observations made during this optimization process, resulting in two potent lead series that demonstrate significant increases in activity. We describe the process of compound elaboration either through the growing out from fragments into adjacent pockets or through the conjoining of overlapping fragments and demonstrate that we have exploited the mobile conserved activation loop, consisting in part of Asp168-Phe169-Gly170 (DFG), to generate significant improvements in potency and kinase selectivity.