PI3K inhibitors are finally coming of age Vanhaesebroeck, Bart; Perry, Matthew W D; Brown, Jennifer R ...
Nature reviews. Drug discovery,
10/2021, Letnik:
20, Številka:
10
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Overactive phosphoinositide 3-kinase (PI3K) in cancer and immune dysregulation has spurred extensive efforts to develop therapeutic PI3K inhibitors. Although progress has been hampered by issues such ...as poor drug tolerance and drug resistance, several PI3K inhibitors have now received regulatory approval - the PI3Kα isoform-selective inhibitor alpelisib for the treatment of breast cancer and inhibitors mainly aimed at the leukocyte-enriched PI3Kδ in B cell malignancies. In addition to targeting cancer cell-intrinsic PI3K activity, emerging evidence highlights the potential of PI3K inhibitors in cancer immunotherapy. This Review summarizes key discoveries that aid the clinical translation of PI3Kα and PI3Kδ inhibitors, highlighting lessons learnt and future opportunities.
Phosphoinositol 3-kinases (PI3Ks) γ and δ are key enzymes in hematopoietic cells and have been seen as high-value targets for the treatment of diseases with inflammatory and immunomodulatory ...components since their discovery and the identification of their roles. In this Perspective we review progress in the application of inhibitors of PI3Kγ and δ to inflammatory and immunological conditions over the past 6 years. We consider progress in the understanding of the roles of PI3Kγ and PI3Kδ in immunology and inflammation, the experience from clinical trials where inhibitors have been tested, and what has been learned about the safety of their use. The extensive medicinal chemistry efforts to discover both isoform selective and dual PI3Kγδ inhibitors are analyzed and detailed. Developments in understanding the structural chemistry of the PI3K enzymes and the factors that govern isoform selectivity are discussed. The effects observed with the known inhibitor compounds in animal models are described.
14-3-3 modulation of the inflammatory response Munier, Claire C.; Ottmann, Christian; Perry, Matthew W.D.
Pharmacological research,
January 2021, 2021-01-00, 20210101, Letnik:
163
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Regulation of inflammation is a central part of the maintenance of homeostasis by the immune system. One important class of regulatory protein that has been shown to have effects on ...the inflammatory process are the 14−3-3 proteins. Herein we describe the roles that have been identified for 14−3-3 in regulation of the inflammatory response. These roles encompass regulation of the response that affect inflammation at the genetic, molecular and cellular levels. At a genetic level 14−3-3 is involved in the regulation of multiple transcription factors and affects the transcription of key effectors of the immune response. At a molecular level many of the constituent parts of the inflammatory process, such as pattern recognition receptors, protease activated receptors and cytokines are regulated through phosphorylation and recognition by 14−3-3 whilst disruption of the recognition processes has been observed to result in clinical syndromes. 14−3-3 is also involved in the regulation of cell proliferation and differentiation, this has been shown to affect the immune system, particularly T- and B-cells. Finally, we discuss how abnormal levels of 14−3-3 contribute to undesirable immune responses and chronic inflammatory conditions.
The lex Scantinia was one of the earliest (and arguably one of the most infamous) laws criminalizing sexual misconduct in Roman society. Modern scholars know little about the specifics of the law ...itself, largely because all evidence for the law, the behaviors it prohibited, and any mechanisms for enforcement/punishment must be gleaned from a few scattered references appearing in a variety of literary sources. This paper examines the literary legacy of the lex Scantinia against the legislative context in which the law may have been created. It suggests that the consensus about what constituted sexual morality and the drive to assert state authority were not necessarily synonymous with a deep commitment to and prioritization of this standard in everyday life.
Historically accessed through two-electron, anionic chemistry, ketones, alcohols, and amines are of foundational importance to the practice of organic synthesis. After placing this work in proper ...historical context, this Article reports the development, full scope, and a mechanistic picture for a strikingly different way of forging such functional groups. Thus, carboxylic acids, once converted to redox-active esters (RAEs), can be utilized as formally nucleophilic coupling partners with other carboxylic derivatives (to produce ketones), imines (to produce benzylic amines), or aldehydes (to produce alcohols). The reactions are uniformly mild, operationally simple, and, in the case of ketone synthesis, broad in scope (including several applications to the simplification of synthetic problems and to parallel synthesis). Finally, an extensive mechanistic study of the ketone synthesis is performed to trace the elementary steps of the catalytic cycle and provide the end-user with a clear and understandable rationale for the selectivity, role of additives, and underlying driving forces involved.
Abstract Background The use of topical agents in the treatment of carcinoma in situ (CIS) of the penis has been well described in the literature. Previous studies have been limited by small sample ...size and imprecise end points. Objective Establish the response rate of 5-fluorouracil (5-FU) and imiquimod (IQ) in the treatment of penile CIS in a large contemporary series in a supranetwork centre. Design, setting, and participants Retrospective review of all primary and recurrent cases of penile CIS treated with 5-FU and IQ identified from a prospective database over a 10-yr period. Therapy was standardised in all cases with application to the lesion for 12 h every 48 h for 28 d. Intervention 5-FU was the first-line therapy, and IQ was the second-line topical agent. Outcome measurements and statistical analysis The primary end point was defined as complete response (CR; ie, resolution of lesion), partial response (PR; ie, lesion reduced in size and or visibility), or no response (NR; ie, no improvement in lesion size and or visibility). The secondary end points included local toxicity and adverse events. No statistical analysis or software was used. Results and limitations A total of 86 patients were diagnosed with CIS of the penis over the 10-yr period. Forty-four (51%) received topical chemotherapy. The mean follow-up was 34 mo. CR to topical chemotherapy was seen in 25 (57%), PR was seen in 6 (13.6%), and NR was seen in the remaining 13 (29.5%) patients. Local toxicity was experienced by 10% of patients, and 12% had an adverse event following application of 5-FU. The retrospective design and short follow-up were the major limitations of this study. Conclusions Topical chemotherapy agents are moderately effective first-line therapy in the treatment of penile CIS. Toxicity and adverse events were few with our treatment protocol. The issues of long-term surveillance and assessment of partial responders remain a challenge. Topical chemotherapy should remain a first-line treatment option for penile CIS.
•High quality building blocks can have a big impact on drug discovery.•Commercial reagents do not satisfy our design criteria or provide sufficient SAR.•Design principles for design of novel building ...blocks are outlined.•Analysing reagent usage is a useful approach to improving our design.•Future perspective: open innovation or collection sharing between companies.
One pragmatic way to improve compound quality, while enhancing and accelerating drug discovery projects, is the ability to access a high quality, novel, diverse building block collection. Here, we outline general principles that should be applied to ensure that a building block collection has the greatest impact on drug discovery projects, by discussing design principles for novel reagents and what types of reagents are popular with medicinal chemists in general. We initiated a program in 2009 to address this, which has already delivered three candidate drugs, and the success of that program provides evidence that focussing on building block design is a useful strategy for drug discovery.
The rational design of novel, high quality building blocks can accelerate drug discovery projects and improve compound quality, but has been overlooked in the medicinal chemistry literature.
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. Analysis of energy-minimized structures for stereo- and regioisomeric sets provided fundamental insight into how dynamic, intramolecular interactions in the 3D conformations of macrocycles may be linked to physicochemical properties and permeability. Combined use of quantitative structure-permeability modeling and the procedure for conformational analysis now, for the first time, provides chemists with a rational approach to design cell-permeable non-peptidic macrocycles with potential for oral absorption.
The human ether-a-go-go related gene (hERG) encodes the pore-forming subunit of the rapid component of the delayed rectifier K(+) channel, Kv11.1, which are expressed in the heart, various brain ...regions, smooth muscle cells, endocrine cells, and a wide range of tumor cell lines. However, it is the role that Kv11.1 channels play in the heart that has been best characterized, for two main reasons. First, it is the gene product involved in chromosome 7-associated long QT syndrome (LQTS), an inherited disorder associated with a markedly increased risk of ventricular arrhythmias and sudden cardiac death. Second, blockade of Kv11.1, by a wide range of prescription medications, causes drug-induced QT prolongation with an increase in risk of sudden cardiac arrest. In the first part of this review, the properties of Kv11.1 channels, including biogenesis, trafficking, gating, and pharmacology are discussed, while the second part focuses on the pathophysiology of Kv11.1 channels.
In this paper, we describe the discovery and optimization of a new chemotype of isoform selective PI3Kγ inhibitors. Starting from an HTS hit, potency and physicochemical properties could be improved ...to give compounds such as 15, which is a potent and remarkably selective PI3Kγ inhibitor with ADME properties suitable for oral administration. Compound 15 was advanced into in vivo studies showing dose-dependent inhibition of LPS-induced airway neutrophilia in rats when administered orally.
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