Targets, Tracers and Translation – Novel Radiopharmaceuticals Boost Nuclear Medicine

This is the fourth Special Issue in Pharmaceuticals within the last six years dealing with aspects of radiopharmaceutical sciences. It demonstrates the significant interest and increasing relevance to ameliorate nuclear medicine imaging with PET or SPECT, and also radiotherapeutical procedures.Numerous targets and mechanisms have been identified and have been under investigation over the previous years, covering many fields of medical and clinical research. This development is well illustrated by the articles in the present issue, including 13 original research papers and one review, covering a broad range of actual research topics in the field of radiopharmaceutical sciences

drug target identification at the crossroad of neuronal apoptosis and survival

ABSTRACTIntroduction: Inappropriate activation of apoptosis may contribute to neurodegeneration, a multifaceted process that results in various chronic disorders, including Alzheimer's and Parkinson's diseases. Several in vitro and in vivo studies demonstrated that neuronal apoptosis is a multi-pathway cell-death program that requires RNA synthesis. Thus, transcriptionally activated genes whose products induce cell death can be triggered by different stimuli and antagonized by neurotrophic factors. Systems biology is now unveiling the series of intracellular signaling pathways and key drug targets at the intersection of neuronal apoptosis and survival.Areas covered: This review introduces a genomic approach that can be used to elucidate the systems biology of neuronal apoptosis and survival, and to rationally select drug targets, no longer oriented to emulate the action of growth factors at the membrane receptor level, but rather to modulate their downstream signals.Expert opinion: The advent of genomics ..

Exploring novel aspects of choline phospholipid metabolism in cancer using metabolomics

Abnormal metabolic phenotypes can be a powerful resource for drug and biomarker discoveries. In this thesis, a metabolomic approach was used to examine several aspects of tumour metabolism with potential clinical applications. In the first part, the metabolic consequences of PIK3CA mutation in MCF10A breast cells were assessed. PIK3CA mutation is oncogenic, and is important for disease progression in many breast tumours. Increased glutaminolysis, fatty acid synthesis, pyruvate entry into the TCA cycle, and decreased glycerophosphocholine (GPC) were identified to be the most prominent phenotypes following knock-in PIK3CA mutation in MCF10A cells. GPC has long been reported as a potential marker for disease progression; however, its functional role in cancer remains unclear. Glycerophosphodiester phosphodiesterase is responsible for the hydrolysis of GPC into choline and glycerol-3 phosphate (G3P), and EDI3 is a member of the glycerophosphodiester phosphodiesterase family associated with metastasis in endometrial cancer patients. Through metabolomic analysis of tumour cell models, EDI3 silencing was found to increase GPC levels and the GPC: phosphocholine ratio. Also, it was demonstrated that EDI3 had an impact on a broader spectrum of metabolic phenotypes, and effects on glycolysis and fatty acid synthesis were also observed. Finally, using 1H HR-MAS-NMR, changes in levels of choline phospholipid metabolites following Colony stimulating factor 1 receptor (CSF1R) inhibitor treatment were investigated in a mouse pancreatic tumour model. CSF1R is important for growth signalling of macrophages in tumours. Phosphocholine levels were found to be associated with disease progression and CSF1R inhibitor treatment. Collectively, these findings highlight a number of novel factors in choline phospholipid metabolism that may be important to tumourigenesis and the development of cancer biomarkers, including the role of glycerophosphodiester phosphodiesterase and macrophage-tumour interaction.Open Acces

Approved and experimental small-molecule oncology kinase inhibitor drugs: a mid-2016 overview

Kinase inhibitor research is a comparatively recent branch of medicinal chemistry and pharmacology and the first small-molecule kinase inhibitor, imatinib, was approved for clinical use only 15 years ago. Since then, 33 more kinase inhibitor drugs have received regulatory approval for the treatment of a variety of cancers and the volume of reports on the discovery and development of kinase inhibitors has increased to an extent where it is now difficult—even for those working in the field—easily to keep an overview of the compounds that are being developed, as currently there are 231 such compounds, targeting 38 different protein and lipid kinases (not counting isoforms), in clinical use or under clinical investigation. The purpose of this review is thus to provide an overview of the biomedical rationales for the kinases being targeted on the one hand, and the design principles, as well as chemical, pharmacological, pharmaceutical, and toxicological kinase inhibitor properties, on the other hand. Two issues that are especially important in kinase inhibitor research, target selectivity and drug resistance, as well as the underlying structural concepts, are discussed in general terms and in the context of relevant kinases and their inhibitors

Chemical Modulation of Phospho-Signaling Pathways Involved in Cancer.

Advancements in our understanding of the molecular causes of cancer have led to the therapeutic targeting of key enzymes involved in cell growth. Kinase inhibitors have been the most successful forms of such targeted therapy for a select group of cancers. However, a comprehensive understanding of the biological roles of individual kinases is necessary for therapies to be effective in a majority of cancers. Thus, the development of selective kinase inhibitors is essential for continued improvement in cancer chemotherapy. Additionally, the exploration of non-kinase targets is indispensable in adding to the toolbox of effective anti-cancer agents. To increase the number of tools available for targeted therapy, we aimed to develop selective inhibitors for critical proteins involved in phospho-signaling pathways. Our studies include the development of an inhibitor of the fusion protein, Bcr-Abl, which is the primary driver of Chronic Myelogenous Leukemia (CML). Most current FDA-approved drugs are ineffective against a resistant form of CML bearing a T315I mutation in the kinase domain of Bcr-Abl. Through a hypothesis based on the prevailing model of selectivity, we developed an extremely selective compound with high potency for both the wild-type and mutant forms of Bcr-Abl. The adaptor protein Grb2 is an under-explored, non-kinase target for the treatment of CML and other cancers. Our efforts for targeting Grb2 centered on the hypothesis that utilizing conformational constraint for inhibitor development could lead to compounds with increased potency due to a lowered entropic cost of binding. Through the systematic development of conformationally constrained cyclic peptides, we identified a novel scaffold for the inhibition of Grb2 with in cellulo efficacy in a CML cell line. Lastly, while protein kinases have been traditionally targeted with small molecules directed to their ATP-binding site, targeting the peptide substrate-binding site of kinases offers an attractive alternative with several advantages. Our efforts attempted to circumvent the problems typically associated with substrate-competitive inhibitors by covalently inhibiting the target Akt1 kinase. As a whole, results from this dissertation should advance the development of potent and selective inhibitors and aid in the understanding of signaling pathways involved in cancer.PHDChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/113580/1/sdphadke_1.pd

In silico Methods for Design of Kinase Inhibitors as Anticancer Drugs

Rational drug design implies usage of molecular modeling techniques such as pharmacophore modeling, molecular dynamics, virtual screening, and molecular docking to explain the activity of biomolecules, define molecular determinants for interaction with the drug target, and design more efficient drug candidates. Kinases play an essential role in cell function and therefore are extensively studied targets in drug design and discovery. Kinase inhibitors are clinically very important and widely used antineoplastic drugs. In this review, computational methods used in rational drug design of kinase inhibitors are discussed and compared, considering some representative case studies

From molecular targets to antitumor immunity

This thesis aimed at the development of strategies that could contribute to the evaluation of the clinical potential of new anticancer therapies. The work was divided into two main sections comprising the development of a therapeutic approach to target cancer genetic vulnerabilities and the development of 3D tumor models incorporating cues from the stromal and immune microenvironments. (...

Novel splice variants derived from the receptor tyrosine kinase superfamily are potential therapeutics for rheumatoid arthritis

INTRODUCTION: Despite the advent of biological therapies for the treatment of rheumatoid arthritis, there is a compelling need to develop alternative therapeutic targets for nonresponders to existing treatments. Soluble receptors occur naturally in vivo, such as the splice variant of the cell surface receptor for vascular endothelial growth factor (VEGF)--a key regulator of angiogenesis in rheumatoid arthritis. Bioinformatics analyses predict that the majority of human genes undergo alternative splicing, generating proteins--many of which may have regulatory functions. The objective of the present study was to identify alternative splice variants (ASV) from cell surface receptor genes, and to determine whether the novel proteins encoded exert therapeutic activity in an in vivo model of arthritis. METHODS: To identify novel splice variants, we performed RT-PCR using an mRNA pool representing major human tissue types and tumors. Novel ASV were identified by alignment of each cloned sequence to its respective genomic sequence in comparison with full-length transcripts. To test whether these ASV have biologic activity, we characterized a subset of them for ligand binding, and for efficacy in an animal model of arthritis. The in vivo study was accomplished using adenoviruses expressing secreted ASV. RESULTS: We cloned 60 novel human ASV from 21 genes, encoding cell surface receptors--many of which are known to be important in the regulation of angiogenesis. The ASV were characterized by exon extension, intron retention and alternative exon utilization. Efficient expression and secretion of selected ASV--corresponding to VEGF receptor type 1, VEGF receptor type 2, VEGF receptor type 3, angiopoietin receptor Tie1, Met (receptor for hepatocyte growth factor), colony-stimulating factor 1 receptor, platelet-derived growth factor receptor beta, fibroblast growth factor receptor 1, Kit, and RAGE--was demonstrated, together with binding to their cognate ligands. Importantly, ASV derived from VEGF receptor type 1 and Tie1, and to a lesser extent from VEGF receptor type 2 and fibroblast growth factor receptor 1, reduced clinical signs of arthritis in vivo. The reduction was paralleled by decreased joint inflammation and destruction. CONCLUSION: The present study shows that unique ASV derived from receptors that play key roles in angiogenesis--namely, VEGF receptor type 1 and, for the first time, Tie1--can markedly reduce arthritis severity. More broadly, our results demonstrate that ASV are a source of novel proteins with therapeutic potential in diseases in which angiogenesis and cellular hyperplasia play a central role, such as rheumatoid arthritis

Alzheimer's disease and neuroinflammation: will new drugs in clinical trials pave the way to a multi-target therapy?

: Despite extensive research, no disease-modifying therapeutic option, able to prevent, cure or halt the progression of Alzheimer's disease [AD], is currently available. AD, a devastating neurodegenerative pathology leading to dementia and death, is characterized by two pathological hallmarks, the extracellular deposits of amyloid beta (Aβ) and the intraneuronal deposits of neurofibrillary tangles (NFTs) consisting of altered hyperphosphorylated tau protein. Both have been widely studied and pharmacologically targeted for many years, without significant therapeutic results. In 2022, positive data on two monoclonal antibodies targeting Aβ, donanemab and lecanemab, followed by the 2023 FDA accelerated approval of lecanemab and the publication of the final results of the phase III Clarity AD study, have strengthened the hypothesis of a causal role of Aβ in the pathogenesis of AD. However, the magnitude of the clinical effect elicited by the two drugs is limited, suggesting that additional pathological mechanisms may contribute to the disease. Cumulative studies have shown inflammation as one of the main contributors to the pathogenesis of AD, leading to the recognition of a specific role of neuroinflammation synergic with the Aβ and NFTs cascades. The present review provides an overview of the investigational drugs targeting neuroinflammation that are currently in clinical trials. Moreover, their mechanisms of action, their positioning in the pathological cascade of events that occur in the brain throughout AD disease and their potential benefit/limitation in the therapeutic strategy in AD are discussed and highlighted as well. In addition, the latest patent requests for inflammation-targeting therapeutics to be developed in AD will also be discussed