Poly(ADP-ribose) polymerases (PARPs) are involved in the regulation of many cellular functions. Three consequences of the activation of PARP1, which is the main isoform of the PARP family, are particularly important for drug development: first, its role in DNA repair; second, its capacity to deplete cellular energetic pools, which culminates in cell dysfunction and necrosis; and third, its capacity to promote the transcription of pro-inflammatory genes. Consequently, pharmacological inhibitors of PARP have the potential to enhance the cytotoxicity of certain DNA-damaging anticancer drugs, reduce parenchymal cell necrosis (for example, in stroke or myocardial infarction) and downregulate multiple simultaneous pathways of inflammation and tissue injury (for example, in circulatory shock, colitis or diabetic complications). The first ultrapotent novel PARP inhibitors have now entered human clinical trials. This article presents an overview of the principal pathophysiological pathways and mechanisms that are governed by PARP, followed by the main structures and therapeutic actions of various classes of novel PARP inhibitors.

Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors

Small G proteins play a central role in the organization of the secre- tory and endocytic pathways. The majority of such small G proteins are members of the Rab family, which are anchored to the bilayer by C-terminal prenyl groups. However, the recruitment of some effectors, including vesicle coat proteins, is mediated by a second class of small G proteins that is unique in having an N-terminal amphipathic helix that becomes available for membrane insertion upon GTP binding. Sar1, Arf1, and Arf6 are the best-characterized members of this ADP-ribosylation factor (Arf ) family. In addition, all eukaryotes contain additional distantly related G proteins, often called Arf like, or Arls. The complete Arf family in humans has 29 members. The roles of these related G proteins are poorly under- stood, but recent work has shown that some are involved in mem- brane traffic or organizing the cytoskeleton. Here we review what is known about all the members of the Arf family, along with the known regulatory molecules that convert them between GDP- and GTP-bound states.

The Small G Proteins of the Arf Family and Their Regulators

Poly(ADP-ribose) polymerase-1 (PARP-1) has been an actively pursued drug discovery target for almost 3 decades. Often referred to as the “guardian angel of DNA”, this abundant nuclear enzyme has been the focus of over 20 medicinal chemistry programs in a wide range of therapeutic areas encompassing stroke, cardiac ischemia, cancer, inflammation, anddiabetes (Figure 1).Despite the great therapeutic potential for this target and the tremendous academic and industrial efforts dedicated to it, only recently have PARP-1 inhibitors made headway in clinical trials. Recent results from several PARP-1 inhibitors in phase II clinical trials for cancer therapyhave attracted the attentionofnationalmedia.Of the several potential therapeutic indications for PARP-1 inhibitors, the two major areas that hold the most promise are ischemia and cancer. This review is structured to provide the readers with a brief summary of the rationale for PARP-1 as a therapeutic target, to explain the PARP-1 inhibitor pharmacophore, and to provide an update on the progress of the PARP-1 drug discovery programs. This Perspective will offer a historical account of the critical PARP-1 publications that instilled the interest of the biopharmaceutical industry in the late 1980s and early 1990s. Furthermore, I will discuss why PARP-1 received somuch attention in the late 1990s and early 2000s followed by the slight decline in themedicinal chemistry efforts today (Figure 1). The major PARP-1 medicinal chemistry programs will be highlighted focusing on the lead generation, lead optimization, candidate selection, and clinical progress.Many aspects of the biological functions of PARP-1 fall outside the scope of this medicinal chemistry review. For this reason, the reader should refer to the following citations for a review of the PARP family of enzymes, the biological functions of poly(ADP-ribose), PARP-1 and intracellular signaling, PARP and DNA repair, PARP and epigenetics, PARP and angiogenesis, and the role of PARP-1 in inflammation. The 30 years of medicinal chemistry on this topic have also afforded some excellent medicinal chemistry reviews, most of which predated the disclosure of clinical candidate structures and recent clinical trial results.

Evolution of Poly(ADP-ribose) Polymerase-1 (PARP-1) Inhibitors. From Concept to Clinic

We disclose the development of a novel series of 2-phenyl-2H-indazole-7-carboxamides as poly(ADP-ribose)polymerase (PARP) 1 and 2 inhibitors. This series was optimized to improve enzyme and cellula...

Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): a novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors.

The syndrome of congenital hypoparathyroidism, mental retardation, facial dysmorphism and extreme growth failure (HRD or Sanjad-Sakati syndrome; OMIM 241410) is an autosomal recessive disorder reported almost exclusively in Middle Eastern populations. A similar syndrome with the additional features of osteosclerosis and recurrent bacterial infections has been classified as autosomal recessive Kenny-Caffey syndrome (AR-KCS; OMIM 244460). Both traits have previously been mapped to chromosome 1q43-44 (refs 5,6) and, despite the observed clinical variability, share an ancestral haplotype, suggesting a common founder mutation. We describe refinement of the critical region to an interval of roughly 230 kb and identification of deletion and truncation mutations of TBCE in affected individuals. The gene TBCE encodes one of several chaperone proteins required for the proper folding of alpha-tubulin subunits and the formation of alpha-beta-tubulin heterodimers. Analysis of diseased fibroblasts and lymphoblastoid cells showed lower microtubule density at the microtubule-organizing center (MTOC) and perturbed microtubule polarity in diseased cells. Immunofluorescence and ultrastructural studies showed disturbances in subcellular organelles that require microtubules for membrane trafficking, such as the Golgi and late endosomal compartments. These findings demonstrate that HRD and AR-KCS are chaperone diseases caused by a genetic defect in the tubulin assembly pathway, and establish a potential connection between tubulin physiology and the development of the parathyroid.

https://www.neonatologie.ugent.be/Sanjad-Sakati%20syndrome.pdf

Mutation of TBCE causes hypoparathyroidism-retardation-dysmorphism and autosomal recessive Kenny-Caffey syndrome.

Poly(ADP-ribose) polymerase-1 (PARP-1), the most prominent member of the PARP family, is a DNA-binding protein that is activated by nicks in DNA occurring during inflammation, ischaemia, neurodegeneration or cancer therapy. Activated PARP-1 consumes NAD+ that is cleaved into nicotinamide and ADP-ribose and polymerises the latter onto nuclear acceptor proteins. This highly energy consuming process is pivotal for the maintenance of genomic stability although over-activation can culminate in cell dysfunction and necrosis. Therefore, PARP-1 is regarded as a promising target for the development of drugs useful in various forms of inflammation, ischaemia–reperfusion injury and as an adjunct in cancer therapy. This review summarises the structural classes of known PARP-1 inhibitors, with a focus on new inhibitors published for this target, between 2002 and July 2004. The chemistry and biological data disclosed in these patent applications are discussed in light of new structural knowledge of the catalytic domain...

New inhibitors of poly(ADP-ribose) polymerase (PARP)

The synthesis, activity and physical properties of two series of novel potent tetrahydro-1(2H)-isoquinolinone based PARP-1 inhibitors are described The new structural classes with a nonplanar ring system interact specifically with the PARP-1 protein at the nicotinamide-binding site

Poly(ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors Based on a Tetrahydro-1(2H)-isoquinolinone Scaffold: Synthesis, Biological Evaluation and X-ray Crystal Structure

La presente invention concerne une serie de derives de pyridone 2,3,5-substitues tels que definis dans les revendications. L'invention concerne egalement des methodes de fabrication desdits composes. Les composes de l'invention sont des inhibiteurs de la poly(adenosine 5'-diphosphate ribose) polymerase (PARP) et sont ainsi utilises comme agents pharmaceutiques, en particulier dans le traitement et/ou la prevention de diverses maladies, y compris les maladies associees au systeme nerveux central et aux troubles cardiovasculaires.

Pyridones substitues inhibiteurs de la poly(adp-ribose) polymerase (parp)

Functional overlap between retinitis pigmentosa 2 protein and the tubulin-specific chaperone cofactor C.

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.

Uwe Schwahn

Author Tools

Chat about Author

Papers

New inhibitors of poly(ADP-ribose) polymerase (PARP)

Poly(ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors Based on a Tetrahydro-1(2H)-isoquinolinone Scaffold: Synthesis, Biological Evaluation and X-ray Crystal Structure

Pyridones substitues inhibiteurs de la poly(adp-ribose) polymerase (parp)

Functional overlap between retinitis pigmentosa 2 protein and the tubulin-specific chaperone cofactor C.