Malignant melanoma is a dangerous skin cancer, accounting for the majority of skin cancer-related deaths. Many patients with this cancer have the V600E mutation in the BRAF gene. This mutation causes constitutive activation of the MAPK/ERK signaling pathway, significantly contributing to the process of carcinogenesis. We discuss the drug design process on the example of a specific BRAF V600E inhibitor, vemurafenib. We begin with the most commonly used drug design methods. The second part of the article focuses on vemurafenib. We analyze the invention of this BRAF V600E inhibitor and its analogue as well as the course of three stages of clinical trials. Then we provide information about other popular drugs for malignant melanoma, i.e. dacarbazine, ipilimumab and dabrafenib, and about the advantages of therapy with the simultaneous use of two inhibitors. Finally, we briefly discuss the role of artificial intelligence in the future of drug design.
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http://dx.doi.org/10.18388/pb.2021_498 | DOI Listing |
J Med Chem
January 2025
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
The Ca/calmodulin-dependent protein kinase II α (CaMKIIα) plays a crucial role in regulating neuronal signaling and higher brain functions, being involved in various brain diseases. Utilization of small molecules targeting the CaMKIIα hub domain has proved to be a promising strategy for specific CaMKIIα modulation and future therapy. Through an structure-based virtual screening campaign, we herein identified 2-arylthiazole-4-carboxylic acids as a new class of high-affinity CaMKIIα hub ligands.
View Article and Find Full Text PDFExpert Opin Drug Discov
January 2025
Centro de Investigación en Reproducción Animal Universidad Autónoma de Tlaxcala - CINVESTAV Tlaxcala, Tlaxcala, México.
Introduction: Existing pharmacotherapies for schizophrenia have not progressed beyond targeting dopamine and serotonin neurotransmission. Rodent models of schizophrenia are a necessary tool for elucidating neuropathological processes and testing potential pharmacotherapies, but positive preclinical results in rodent models often do not translate to positive results in the clinic.
Areas Covered: The authors reviewed PubMed for studies that applied rodent behavioral models of schizophrenia to assess the antipsychotic potential of several novel pharmacotherapies currently under investigation.
Proc Natl Acad Sci U S A
February 2025
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, People's Republic of China.
Carrier-free nanomedicines exhibited significant potential in elevating drug efficacy and safety for tumor management, yet their self assembly typically relied on chemical modifications of drugs or the incorporation of surfactants, thereby compromising the drug's inherent pharmacological activity. To address this challenge, we proposed a triethylamine (TEA)-mediated protonation-deprotonation strategy that enabled the adjustable-proportion self assembly of dual drugs without chemical modification, achieving nearly 100% drug loading capacity. Molecular dynamic simulations, supported by experiment evidence, elucidated the underlying self-assembly mechanism.
View Article and Find Full Text PDFChemMedChem
January 2025
NRG Therapeutics, Stevenage, United Kingdom.
Optimizing pharmacokinetics is an integral part of drug design, albeit a lesser understood one from the medicinal chemist's perspective. Over the years, molecular tools and experimental strategies have been developed to better understand the fate of compounds. Among these, the use of aminobenzotriazole (ABT), elacridar and bile-duct cannulated rats have been instrumental in gaining valuable PK insights, with a direct impact on drug design.
View Article and Find Full Text PDFJAMA Netw Open
January 2025
Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.
Importance: The net clinical effect of early vs later direct oral anticoagulant (DOAC) initiation after atrial fibrillation-associated ischemic stroke is unclear.
Objective: To investigate whether early DOAC treatment is associated with a net clinical benefit (NCB).
Design, Setting, And Participants: This was a post hoc analysis of the Early Versus Late Initiation of Direct Oral Anticoagulants in Post-Ischaemic Stroke Patients With Atrial Fibrillation (ELAN) open-label randomized clinical trial conducted across 103 sites in 15 countries in Europe, the Middle East, and Asia between November 6, 2017, and September 12, 2022, with a 90-day follow-up.
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