Dwaipayan Dey, Srestha Ghosh, Divya Mirgh, Siva Parsad Panda, Niraj Kumar Jha, Saurabh Kumar Jha
Prostate cancer (PCa) is the second most common and fifth most aggressive neoplasm among men worldwide. In the last decade, extracellular vesicle (EV) research has decoded multiple unsolved cancer-related mysteries. EVs can be classified as microvesicles, apoptotic bodies, and exosomes, among others. Exosomes play a key role in cellular signaling. Their internal cargos (nucleic acids, proteins, lipids) influence the recipient cell. In PCa, the exosome is the regulator of cancer progression. It is also a promising theranostics tool for PCa...
September 28, 2023: Drug Discovery Today
Alexander Schuhmacher, Markus Hinder, Nikolaj Boger, Oliver Gassmann, Dominik Hartl
No abstract text is available yet for this article.
September 27, 2023: Drug Discovery Today
Yu Wang, Mengmeng Sang, Li Feng, Claudia Gragnoli, Christopher Griffin, Rongling Wu
Because drug response is multifactorial, graph models are uniquely powerful for comprehending its genetic architecture. We deconstruct drug response into many different and interdependent sub-traits, with each sub-trait controlled by multiple genes that act and interact in a complicated manner. The outcome of drug response is the consequence of multileveled intertwined interactions between pleiotropic effects and epistatic effects. Here, we propose a general statistical physics framework to chart the 3D geometric network that codes how epistasis pleiotropically influences a complete set of sub-traits to shape body-drug interactions...
September 25, 2023: Drug Discovery Today
Arjun Jain, Ira Jain
Elevated endothelin-1 (ET-1) has been implicated in several diseases including preeclampsia, where it causes the induction of hypertension, oxidative stress, endoplasmic reticulum stress, microvascular dysfunction and tissue damage in different organs. ET-traps are Fc-fusion proteins with a design based on the physiological receptors of ET-1. This paper discusses the potential use of ET-traps as a therapeutic for preeclampsia. ET-traps potently bind and sequester pathologically elevated ET-1 to significantly reduce different markers of pathology to non-disease levels with no toxicity...
September 22, 2023: Drug Discovery Today
Jingjing Xu, Xiaohua Jiang, Suowen Xu
Hypertension is reaching epidemic proportions worldwide and is a significant public health concern. However, ∼15% of patients with hypertension continue to experience elevated blood pressure, even after taking antihypertensive medications [such as angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs), dihydropyridine calcium channel blockers (CCBs) and thiazide diuretics], a condition referred to as resistant hypertension (RH). Within the complex realm of blood pressure regulation and vascular function, endothelin-1 (ET-1), a potent vasoconstrictor, has a pivotal role...
September 22, 2023: Drug Discovery Today
Rajeev Sharma, Priya Shrivastava, Laxmikant Goutam, Udita Agrawal, S Mohana Lakshmi, Suresh P Vyas
Various polymeric materials have been investigated to produce unique modes of delivery for drug modules to achieve either temporal or spatial control of bioactives delivery. However, after intravenous administration, phagocytic cells quickly remove these nanostructures from the systemic circulation via the reticuloendothelial system (RES). To overcome these concerns, ecofriendly block copolymers are increasingly being investigated as innovative carriers for the delivery of bioactives. In this review, we discuss the design, fabrication techniques, and recent advances in the development of block copolymers and their applications as drug carrier systems to improve the physicochemical and pharmacological attributes of bioactives...
September 22, 2023: Drug Discovery Today
Zonghui Ma, Andrew A Bolinger, Jia Zhou
Regulated induced proximity targeting chimeras (RIPTACs), a new class of heterobifunctional molecules, show promise in specifically targeting and eliminating cancer cells while leaving healthy cells unharmed. As a groundbreaking drug discovery approach, RIPTACs work by forming a stable complex with two proteins, one specifically found in cancer cells (target protein, TP) and the other pan-essential for cell survival (effector protein, EP), selectively disrupting the function of the EP in cancer cells and causing cell death...
September 19, 2023: Drug Discovery Today
Maurice Perrinjaquet, C Richard Schlegel
Neoantigen cancer vaccines harbor promise as next-generation immuno-oncology therapies, whereby cancer vaccines are tailored to the patient's tumor antigen and represent the future of personalized cancer therapy. While several biotech companies have ongoing development programs, little has been published about the true commercial potential of these innovative therapies and the challenges these products will face upon regulatory approval. In this paper, we provide an overview of neoantigen cancer vaccine development programs and discuss the commercial environment these therapies will face upon launch...
September 18, 2023: Drug Discovery Today
François-Xavier Blaudin de Thé, Claire Baudier, Renan Andrade Pereira, Céline Lefebvre, Philippe Moingeon
High-throughput computational platforms are being established to accelerate drug discovery. Servier launched the Patrimony platform to harness computational sciences and artificial intelligence (AI) to integrate massive multimodal data from internal and external sources. Patrimony has enabled researchers to prioritize therapeutic targets based on a deep understanding of the pathophysiology of immuno-inflammatory diseases. Herein, we share our experience regarding main challenges and critical success factors faced when industrializing the platform and broadening its applications to neurological diseases...
September 15, 2023: Drug Discovery Today
Joab Williamson, Alexander James Spicer
This study examines the effect of the FDA's Fast Track Designation (FTD) on biotech company share prices. Using an event-study approach on 25 FTD announcements between June 2019 and June 2020, notable short- and long-term share price hikes were observed, with a 5-day cumulative average abnormal returns of 21.59%, 30-day at 38.34%, 1-year at 76.64% and 3-year at 111.37% against the XBI benchmark. These surges surpass prior research findings, indicating stronger investor reactions. The role of the COVID-19 pandemic as a confounder is discussed...
September 14, 2023: Drug Discovery Today
Yanyan Qu, Ting Li, Zhichao Liu, Dongying Li, Weida Tong
Drug-induced cardiotoxicity (DICT) is a leading cause of drug trial failure and discontinuation. Current drug annotations for cardiotoxicity largely focus on individual outcomes or mechanisms. Considering the broad spectrum of adverse cardiac events, we developed Drug-Induced Cardiotoxicity Rank (DICTrank) using FDA labeling and comprehensively classified 1318 human drugs into four categories: Most-DICT-Concern (n=341), Less-DICT-Concern (n=528), No-DICT-Concern (n=343), and Ambiguous-DICT-Concern (n=106). Notably, DICTrank covers diverse therapeutic categories, of which several were enriched with Most-DICT-Concern drugs, such as antineoplastic agents, sex hormones, anti-inflammatory drugs, beta-blockers, and cardiac therapy...
September 13, 2023: Drug Discovery Today
Benjamin R Helmold, Kate E Pauss, P Hande Ozdinler
Transactive response DNA binding protein of 43 kDa (TDP-43) pathology is a common proteinopathy observed among a broad spectrum of patients with neurodegenerative disease, regardless of the mutation. This suggests that protein-protein interactions of TDP-43 with other proteins may in part be responsible for the pathology. To gain better insights, we investigated TDP-43-binding proteins in each domain and correlated these interactions with canonical pathways. These investigations revealed key cellular events that are involved and are important at each domain and suggested previously identified compounds to modulate key aspects of these canonical pathways, suggesting that personalized medicine approaches that focus on perturbed cellular mechanisms are feasible in the near future...
September 13, 2023: Drug Discovery Today
Yingying Mu, Lijie Zhao, Lan Shen
Medication adherence in pediatric patients is a key factor in drug development and dosage form design. High medication adherence is not only important to achieve the expected treatment effects but can also effectively reduce medical costs. It is an ongoing task to accurately identify differences in medication adherence between children and adults and analyze the factors related to pediatric medication adherence. This is necessary to guide the development of pediatric drugs. This review focuses on factors that influence medication adherence as well as pharmaceutical design strategies to improve adherence...
September 12, 2023: Drug Discovery Today
Hongmei Zheng, Gangjian Li, Jingli Min, Xiangwei Xu, Wenhai Huang
Recently, targeted protein degradation technologies based on lysosomal pathways have been developed. Lysosome-based targeted protein degradation technology has a broad range of substrates and the potential to degrade intracellular and extracellular proteins, protein aggregates, damaged organelles and non-protein molecules. Thus, they hold great promise for drug R&D. This study has focused on the biogenesis of lysosomes, their basic functions, lysosome-associated diseases and targeted protein degradation technologies through the lysosomal pathway...
September 12, 2023: Drug Discovery Today
Shubhangi Saxena, Neha Dagar, Vishwadeep Shelke, Maciej Lech, Pragyanshu Khare, Anil Bhanudas Gaikwad
As a high-metabolic-rate organ, the kidney exhibits metabolic reprogramming (MR) in various disease states. Given the 860.8 million cases of kidney disease worldwide in 2017, understanding the specific bioenergetic pathways involved and developing targeted interventions are vital needs. The reprogramming of metabolic pathways (glucose metabolism, amino acid metabolism, etc.) has been observed in kidney disease. Therapies targeting these specific pathways have proven to be an efficient approach for retarding kidney disease progression...
September 8, 2023: Drug Discovery Today
Amr A A Abd El-Aal, Fairen A Jayakumar, Kavita Reginald
Cryptides are a subfamily of bioactive peptides embedded latently in their parent proteins and have multiple biological functions. Cationic cryptides could be used as modern drugs in both infectious diseases and cancers because their mechanism of action is less likely to be affected by genetic mutations in the treated cells, therefore addressing a current unmet need in these two areas of medicine. In this review, we present the current understanding of cryptides, methods to mine them sustainably using available online databases and prediction tools, with a particular focus on their antimicrobial and anticancer potential, and their potential applicability in a clinical setting...
September 7, 2023: Drug Discovery Today
Carolina von Essen, David Luedeker
Pharmaceutical co-crystals represent a growing class of crystal forms in the context of pharmaceutical science. They are attractive to pharmaceutical scientists because they significantly expand the number of crystal forms that exist for an active pharmaceutical ingredient and can lead to improvements in physicochemical properties of clinical relevance. At the same time, machine learning is finding its way into all areas of drug discovery and delivers impressive results. In this review, we attempt to provide an overview of machine learning, deep learning and network-based recommendation approaches applied to pharmaceutical co-crystallization...
September 7, 2023: Drug Discovery Today
Renaud Prudent, Hugues Lemoine, Jarrod Walsh, Didier Roche
Affinity selection mass spectrometry (AS-MS) has gained momentum in drug discovery. This review summarizes how this technology has slowly risen as a new paradigm in hit identification and its potential synergy with DNA encoded library technology. It presents an overview of the recent results on challenging targets and perspectives on new areas of research, such as RNA targeting with small molecules. The versatility of the approach is illustrated and strategic drivers discussed in terms of the experience of a small-medium CRO and a big pharma organization...
September 1, 2023: Drug Discovery Today
Christofer S Tautermann, Jens M Borghardt, Roland Pfau, Matthias Zentgraf, Nils Weskamp, Achim Sauer
The suitability of small molecules as oral drugs is often assessed by simple physicochemical rules, the application of ligand efficiency scores or by composite scores based on physicochemical compound properties. These rules and scores are empirical and typically lack mechanistic background, such as information on pharmacokinetics (PK). We introduce new types of Compound Quality Scores (CQS, specifically called dose scores and cmax scores), which explicitly include predicted or, when available, experimental PK parameters and combine these with on-target potency...
September 1, 2023: Drug Discovery Today
Ketki Bhise, Navnath S Gavande, Arun K Iyer
Current treatment strategies for triple-negative breast cancer (TNBC) are based upon conventional chemotherapy, immunotherapy, or a combination of both. The treatment regimen for chemotherapy is often a combination of two or more drugs, either dose dense or low dose for synergy. Anthracyclines, alkylating agents, antimicrotubule agents, and antimetabolites for early-stage TNBC; and antimetabolites, non-taxane microtubule inhibitors, and cross-linker platinums for late-stage TNBC are usually administered in the clinical setting...
September 1, 2023: Drug Discovery Today
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