The ChEMBL Database in 2023: a drug discovery platform spanning multiple bioactivity data types and time periods

Nucleic Acids Research, Год журнала: 2023, Номер 52(D1), С. D1180 - D1192

Опубликована: Ноя. 2, 2023

Abstract ChEMBL (https://www.ebi.ac.uk/chembl/) is a manually curated, high-quality, large-scale, open, FAIR and Global Core Biodata Resource of bioactive molecules with drug-like properties, previously described in the 2012, 2014, 2017 2019 Nucleic Acids Research Database Issues. Since its introduction 2009, ChEMBL’s content has changed dramatically size diversity data types. Through incorporation multiple new datasets from depositors since update, now contains slightly more bioactivity deposited vs extracted literature. In collaboration EUbOPEN consortium, chemical probe regularly into ChEMBL. Release 27 made curated available for compounds screened potential anti-SARS-CoV-2 activity several large-scale drug repurposing screens. addition, patent have been added to latest releases, various features incorporated, including Natural Product likeness score, updated flags Products, flag Chemical Probes, initial annotation action type ∼270 000 measurements.

Язык: Английский

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Exploring the next generation of antibody–drug conjugates

Nature Reviews Clinical Oncology, Год журнала: 2024, Номер 21(3), С. 203 - 223

Опубликована: Янв. 8, 2024

Язык: Английский

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Targeted protein degradation: from mechanisms to clinic

Nature Reviews Molecular Cell Biology, Год журнала: 2024, Номер 25(9), С. 740 - 757

Опубликована: Апрель 29, 2024

Язык: Английский

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Targeted protein degrader development for cancer: advances, challenges, and opportunities

Trends in Pharmacological Sciences, Год журнала: 2023, Номер 44(5), С. 303 - 317

Опубликована: Апрель 13, 2023

Anticancer-targeted therapies inhibit various kinases implicated in cancer and have been used clinical settings for decades. However, many cancer-related targets are proteins without catalytic activity difficult to target using traditional occupancy-driven inhibitors. Targeted protein degradation (TPD) is an emerging therapeutic modality that has expanded the druggable proteome treatment. With entry of new-generation immunomodulatory drugs (IMiDs), selective estrogen receptor degraders (SERDs), proteolysis-targeting chimera (PROTAC) into trials, field TPD seen explosive growth past 10 years. Several challenges remain need be tackled increase successful translation drugs. We present overview global landscape trials over decade summarize profiles In addition, we highlight opportunities development effective future translation.

Язык: Английский

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Roles and inhibitors of FAK in cancer: current advances and future directions

Frontiers in Pharmacology, Год журнала: 2024, Номер 15

Опубликована: Фев. 12, 2024

Focal adhesion kinase (FAK) is a non-receptor tyrosine that exhibits high expression in various tumors and associated with poor prognosis. FAK activation promotes tumor growth, invasion, metastasis, angiogenesis via both kinase-dependent kinase-independent pathways. Moreover, crucial for sustaining the microenvironment. The inhibition of impedes tumorigenesis, drug resistance cancer. Therefore, developing targeted inhibitors against presents promising therapeutic strategy. To date, numerous inhibitors, including IN10018, defactinib, GSK2256098, conteltinib, APG-2449, have been developed, which demonstrated positive anti-tumor effects preclinical studies are undergoing clinical trials several types tumors. many novel currently to advance therapy aberrantly activated FAK. benefits degraders, especially terms their scaffold function, increasingly evident, holding potential future exploration breakthroughs. This review aims clarify FAK's role cancer, offering comprehensive overview current status prospects FAK-targeted combination approaches. goal provide valuable insights advancing anti-cancer treatment strategies.

Язык: Английский

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Characteristic roadmap of linker governs the rational design of PROTACs

Acta Pharmaceutica Sinica B, Год журнала: 2024, Номер 14(10), С. 4266 - 4295

Опубликована: Апрель 11, 2024

Proteolysis targeting chimera (PROTAC) technology represents a groundbreaking development in drug discovery, leveraging the ubiquitin‒proteasome system to specifically degrade proteins responsible for disease. PROTAC is characterized by its unique heterobifunctional structure, which comprises two functional domains connected linker. The linker plays pivotal role determining PROTAC's biodegradative efficacy. Advanced and rationally designed linkers are under development. Nonetheless, correlation between characteristics efficacy remains under-investigated. Consequently, this study will present multidisciplinary analysis of their impact on efficacy, thereby guiding rational design linkers. We primarily discuss structural types linkers, optimization strategies used design. Furthermore, we how factors like length, group type, flexibility, linkage site affect biodegradation efficiency PROTACs. believe that work contribute towards advancement research area.

Язык: Английский

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Revolutionizing Cancer Treatment: Unleashing the Power of Viral Vaccines, Monoclonal Antibodies, and Proteolysis-Targeting Chimeras in the New Era of Immunotherapy

ACS Omega, Год журнала: 2024, Номер unknown

Опубликована: Фев. 5, 2024

In the realm of cancer immunotherapy, a profound evolution has ushered in sophisticated strategies that encompass both traditional vaccines and emerging viral vaccines. This comprehensive Review offers an in-depth exploration methodologies, clinical applications, success stories, future prospects these approaches. Traditional have undergone significant advancements utilizing diverse modalities such as proteins, peptides, dendritic cells. More recent innovations focused on physiological mechanisms enabling human body to recognize combat precancerous malignant cells, introducing specific markers like peptide-based anticancer targeting tumor-associated antigens. Moreover, vaccines, leveraging engineered viruses stimulate immune responses against antigens, exhibit substantial promise inducing robust enduring immunity. Integration with complementary therapeutic methods, including monoclonal antibodies, adjuvants, radiation therapy, not only improved survival rates but also deepened our understanding virulence. Recent strides vaccine design, encompassing oncolytic viruses, virus-like particles, vectors, mark frontier innovation. While advances hold immense potential, critical challenges must be addressed, for evasion, potential off-target effects, optimization genomes. landscape noteworthy take spotlight from use immunomodulatory agents enhancement innate adaptive collaboration. The emergence proteolysis-targeting chimeras (PROTACs) precision tools therapy is particularly exciting. With focus various cancers, melanoma formidable solid tumors, this critically assesses types mechanisms, barriers efficacy, safety profiles, immune-related adverse events, providing nuanced perspective underlying involving cytotoxic T natural killer underscores transformative cutting-edge technologies studies, molecular sequencing, artificial intelligence advancing field These expedite progress emphasize multidimensional rapidly evolving nature research, affirming its significance broader context therapy.

Язык: Английский

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Multicomponent reactions (MCRs) yielding medicinally relevant rings: a recent update and chemical space analysis of the scaffolds

RSC Advances, Год журнала: 2025, Номер 15(2), С. 1447 - 1489

Опубликована: Янв. 1, 2025

We have reviewed the recently reported multicomponent reactions (MCRs) yielding cyclic frameworks in a single pot from simple building blocks under mild conditions. These MCRs may prove to be useful for drug discovery projects.

Язык: Английский

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Targeted Protein Degradation: Advances, Challenges, and Prospects for Computational Methods

Journal of Chemical Information and Modeling, Год журнала: 2023, Номер 63(17), С. 5408 - 5432

Опубликована: Авг. 21, 2023

The therapeutic approach of targeted protein degradation (TPD) is gaining momentum due to its potentially superior effects compared with inhibition. Recent advancements in the biotech and pharmaceutical sectors have led development compounds that are currently human trials, some showing promising clinical results. However, use computational tools TPD still limited, as it has distinct characteristics traditional drug design methods. involves creating a ternary structure (protein-degrader-ligase) responsible for biological function, such ubiquitination subsequent proteasomal degradation, which depends on spatial orientation interest (POI) relative E2-loaded ubiquitin. Modeling this necessitates unique blend initially developed small molecules (e.g., docking) biologics protein-protein interaction modeling). Additionally, degrader molecules, particularly heterobifunctional degraders, generally larger than conventional molecule drugs, leading challenges determining drug-like properties like solubility permeability. Furthermore, catalytic nature makes occupancy-based modeling insufficient. consists multiple interconnected yet steps, POI binding, E3 ligase interactions, ubiquitination, along properties. A comprehensive set needed address dynamic induced proximity complex implications ubiquitination. In Perspective, we discuss current state TPD. We start by describing series steps involved process experimental methods used characterize them. Then, delve into detailed analysis employed also present an integrative proven successful impact project decisions. Finally, examine future prospects areas greatest potential impact.

Язык: Английский

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Research in the Field of Drug Design and Development

Pharmaceuticals, Год журнала: 2023, Номер 16(9), С. 1283 - 1283

Опубликована: Сен. 11, 2023

The processes used by academic and industrial scientists to discover new drugs have recently experienced a true renaissance, with many exciting techniques being developed over the past 5-10 years alone. Drug design discovery, search for safe well-tolerated compounds, as well ineffectiveness of existing therapies, society's insufficient knowledge concerning prophylactics pharmacotherapy most common diseases today, comprise serious challenge. This can influence not only quality human life, but also health whole societies, which became evident during COVID-19 pandemic. In general, process drug development consists three main stages: preclinical using cell-based animal models/tests, clinical trials on humans and, finally, forward moving toward step obtaining regulatory approval, in order market potential drug. this review, we will attempt outline first important consecutive phases development, based experience cooperating complementary centers Visegrád group; i.e., Medical University Lublin, Poland, Masaryk Brno, Czech Republic, Comenius Bratislava, Slovak Republic.

Язык: Английский

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