The three endogenous gaseous transmitters - nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) - regulate a number of key biological functions. Emerging data have revealed several new mechanisms for each of these three gasotransmitters in tumour biology. It is now appreciated that they show bimodal pharmacological character in cancer, in that not only the inhibition of their biosynthesis but also elevation of their concentration beyond a certain threshold can exert anticancer effects. This Review discusses the role of each gasotransmitter in cancer and the effects of pharmacological agents - some of which are in early-stage clinical studies - that modulate the levels of each gasotransmitter. A clearer understanding of the pharmacological character of these three gases and the mechanisms underlying their biological effects is expected to guide further clinical translation.

/pdf/gasotransmitters-in-cancer-from-pathophysiology-to-25czmrkjfs.pdf

Gasotransmitters in cancer: from pathophysiology to experimental therapy

Integrins are activatable molecules that are involved in adhesion and signalling. Of the 24 known human integrins, 3 are currently targeted therapeutically by monoclonal antibodies, peptides or small molecules: drugs targeting the platelet αIIbβ3 integrin are used to prevent thrombotic complications after percutaneous coronary interventions, and compounds targeting the lymphocyte α4β1 and α4β7 integrins have indications in multiple sclerosis and inflammatory bowel disease. New antibodies and small molecules targeting β7 integrins (α4β7 and αEβ7 integrins) and their ligands are in clinical development for the treatment of inflammatory bowel diseases. Integrin-based therapeutics have shown clinically significant benefits in many patients, leading to continued medical interest in the further development of novel integrin inhibitors. Of note, almost all integrin antagonists in use or in late-stage clinical trials target either the ligand-binding site or the ligand itself.

Integrin-based therapeutics: biological basis, clinical use and new drugs

Integrins are cell adhesion and signalling proteins crucial to a wide range of biological functions. Effective marketed treatments have successfully targeted integrins αIIbβ3, α4β7/α4β1 and αLβ2 for cardiovascular diseases, inflammatory bowel disease/multiple sclerosis and dry eye disease, respectively. Yet, clinical development of others, notably within the RGD-binding subfamily of αv integrins, including αvβ3, have faced significant challenges in the fields of cancer, ophthalmology and osteoporosis. New inhibitors of the related integrins αvβ6 and αvβ1 have recently come to the fore and are being investigated clinically for the treatment of fibrotic diseases, including idiopathic pulmonary fibrosis and nonalcoholic steatohepatitis. The design of integrin drugs may now be at a turning point, with opportunities to learn from previous clinical trials, to explore new modalities and to incorporate new findings in pharmacological and structural biology. This Review intertwines research from biological, clinical and medicinal chemistry disciplines to discuss historical and current RGD-binding integrin drug discovery, with an emphasis on small-molecule inhibitors of the αv integrins. Integrins are key signalling molecules that are present on the surface of subsets of cells and are therefore good potential therapeutic targets. In this Review, Hatley and colleagues discuss the development of integrin inhibitors, particularly the challenges in developing inhibitors for integrins that contain an αv-subunit, and suggest how these challenges could be addressed.

/pdf/emerging-therapeutic-opportunities-for-integrin-inhibitors-4jteddo6dj.pdf

Emerging therapeutic opportunities for integrin inhibitors.

Integrins are a family of transmembrane glycoprotein signaling receptors that can transmit bioinformation bidirectionally across the plasma membrane. Integrin αIIbβ3 is expressed at a high level in platelets and their progenitors, where it plays a central role in platelet functions, hemostasis, and arterial thrombosis. Integrin αIIbβ3 also participates in cancer progression, such as tumor cell proliferation and metastasis. In resting platelets, integrin αIIbβ3 adopts an inactive conformation. Upon agonist stimulation, the transduction of inside-out signals leads integrin αIIbβ3 to switch from a low- to high-affinity state for fibrinogen and other ligands. Ligand binding causes integrin clustering and subsequently promotes outside-in signaling, which initiates and amplifies a range of cellular events to drive essential platelet functions such as spreading, aggregation, clot retraction, and thrombus consolidation. Regulation of the bidirectional signaling of integrin αIIbβ3 requires the involvement of numerous interacting proteins, which associate with the cytoplasmic tails of αIIbβ3 in particular. Integrin αIIbβ3 and its signaling pathways are considered promising targets for antithrombotic therapy. This review describes the bidirectional signal transduction of integrin αIIbβ3 in platelets, as well as the proteins responsible for its regulation and therapeutic agents that target integrin αIIbβ3 and its signaling pathways.

/pdf/platelet-integrin-aiibb3-signal-transduction-regulation-and-1cmbbd9oqk.pdf

Platelet integrin αIIbβ3: signal transduction, regulation, and its therapeutic targeting

Antiplatelet drugs, such as aspirin, P2Y12 antagonists, and glycoprotein (GP) IIb/IIIa inhibitors, have proved to be successful in reducing the morbidity and mortality associated with arterial thrombosis. These agents are, therefore, the cornerstone of therapy for patients with acute coronary syndromes. However, these drugs all carry an inherent risk of bleeding, which is associated with adverse cardiovascular outcomes and mortality. Thus, the potential benefits of more potent, conventional antiplatelet drugs are likely be offset by the increased risk of bleeding. Data from experiments in vivo have highlighted potentially important differences between haemostasis and thrombosis, raising the prospect of developing new antiplatelet drugs that are not associated with bleeding. Indeed, in preclinical studies, several novel antiplatelet therapies that seem to inhibit thrombosis while maintaining haemostasis have been identified. These agents include inhibitors of phosphatidylinositol 3-kinase-β (PI3Kβ), protein disulfide-isomerase, activated GPIIb/IIIa, GPIIb/IIIa outside-in signalling, protease-activated receptors, and platelet GPVI-mediated adhesion pathways. In this Review, we discuss how a therapeutic ceiling has been reached with existing antiplatelet drugs, whereby increased potency is offset by elevated bleeding risk. The latest advances in our understanding of thrombus formation have informed the development of new antiplatelet drugs that are potentially safer than currently available therapies.

Current and future antiplatelet therapies: emphasis on preserving haemostasis

Objective— Treatment of myocardial infarction within the first 1 to 2 hours with a thrombolytic agent, percutaneous coronary intervention, or an αIIbβ3 antagonist decreases mortality and the later development of heart failure. We previously reported on a novel small molecule αIIbβ3 antagonist, RUC-2, that has a unique mechanism of action. We have now developed a more potent and more soluble congener of RUC-2, RUC-4, designed to be easily administered intramuscularly by autoinjector to facilitate its use in the prehospital setting. Here, we report the properties of RUC-4 and the antiplatelet and antithrombotic effects of RUC-2 and RUC-4 in animal models. Approach and Results— RUC-4 was ≈20% more potent than RUC-2 in inhibiting human ADP-induced platelet aggregation and much more soluble in aqueous solutions (60–80 mg/mL). It shared RUC-2’s specificity for αIIbβ3 versus αVβ3, did not prime the receptor to bind fibrinogen, or induce changes in β3 identified by a conformation-specific monoclonal antibody. Both RUC-2 and RUC-4 prevented FeCl 3 -induced thrombotic occlusion of the carotid artery in mice and decreased microvascular thrombi in response to laser injury produced by human platelets infused into transgenic mice containing a mutated von Willebrand factor that reacts with human but not mouse platelets. Intramuscular injection of RUC-4 in nonhuman primates at 1.9 and 3.85 mg/kg led to complete inhibition of platelet aggregation within 15 minutes, with dose-dependent return of platelet aggregation after 4.5 to 24 hours. Conclusions— RUC-4 has favorable biochemical, pharmacokinetic, pharmacodynamic, antithrombotic, and solubility properties as a prehospital therapy of myocardial infarction, but the possibility of increased bleeding with therapeutic doses remains to be evaluated.

RUC-4: A Novel αIIbβ3 Antagonist for Prehospital Therapy of Myocardial Infarction

The present invention relates to compounds and compositions of Formula P useful for inhibiting and/or reducing platelet deposition, adhesion and/or aggregation. The definitions of variables A, B, R 2 , R 3 , R 4 , R a , R a ′, R b , R b ′, R c , R d , R d ′, R e , and R e ′ are provided in the disclosure. The present invention further relates to methods for the treatment or prophylaxis of thrombotic disorders, including stroke, myocardial infarction, unstable angina, peripheral vascular disease, abrupt closure following angioplasty or stent placement and thrombosis as a result of vascular surgery.

7-(piperazin-1-yl)-5H-[1,3,4]thiadiazolo[3,2-A]pyrimidin-5-ones for the treatment of thrombotic disorders

The present invention relates to compounds and compositions useful for inhibiting and/or reducing platelet deposition, adhesion and/or aggregation The present invention further relates to methods for the treatment or prophylaxis of thrombotic disorders, including stroke, myocardial infarction, unstable angina, peripheral vascular disease, abrupt closure following angioplasty or stent placement and thrombosis as a result of vascular surgery

Oxadiazolo[3,2-A]pyrimidines and thiadiazolo[3,2-A]pyrimidines

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Craig Thomas

Author Tools

Chat about Author

Papers

RUC-4: A Novel αIIbβ3 Antagonist for Prehospital Therapy of Myocardial Infarction

7-(piperazin-1-yl)-5H-[1,3,4]thiadiazolo[3,2-A]pyrimidin-5-ones for the treatment of thrombotic disorders

Oxadiazolo[3,2-A]pyrimidines and thiadiazolo[3,2-A]pyrimidines