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1.
Eur J Med Chem ; 229: 114054, 2022 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-34959172

RESUMO

The human kinome plays a crucial role in several pathways. Its dysregulation has been linked to diverse central nervous system (CNS)-related disorders with a drastic impact on the aging population. Among them, tauopathies, such as Alzheimer's Disease (AD) and Frontotemporal Lobar degeneration (FTLD-tau), are neurodegenerative disorders pathologically defined by the presence of hyperphosphorylated tau-positive intracellular inclusions known as neurofibrillary tangles (NFTs). Compelling evidence has reported the great potential of the simultaneous modulation of multiple protein kinases (PKs) involved in abnormal tau phosphorylation through a concerted pharmacological approach to achieve a superior therapeutic effect relative to classic "one target, one drug" approaches. Here, we report on the identification and characterization of ARN25068 (4), a low nanomolar and well-balanced dual GSK-3ß and FYN inhibitor, which also shows inhibitory activity against DYRK1A, an emerging target in AD and tauopathies. Computational and X-Ray studies highlight compound 4's typical H-bonding pattern of ATP-competitive inhibitors at the binding sites of all three PKs. In a tau phosphorylation assay on Tau0N4R-TM-tGFP U2OS cell line, 4 reduces the extent of tau phosphorylation, promoting tau-stabilized microtubule bundles. In conclusion, this compound emerges as a promising prototype for further SAR explorations to develop potent and well-balanced triple GSK-3ß/FYN/DYRK1A inhibitors to tackle tau hyperphosphorylation.


Assuntos
Glicogênio Sintase Quinase 3 beta/metabolismo , Fármacos Neuroprotetores/síntese química , Inibidores de Proteínas Quinases/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-fyn/antagonistas & inibidores , Tauopatias/tratamento farmacológico , Sítios de Ligação , Avaliação Pré-Clínica de Medicamentos , Humanos , Microtúbulos/metabolismo , Modelos Moleculares , Emaranhados Neurofibrilares/metabolismo , Fármacos Neuroprotetores/farmacologia , Fosforilação , Ligação Proteica , Conformação Proteica , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-Atividade , Proteínas tau/metabolismo , Quinases Dyrk
2.
Front Digit Health ; 4: 1082884, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36620183

RESUMO

Introduction: Breast cancer is one of the most common cancer among Indian women, with an incidence of 25.8 per 100,000 women according to the Ministry of Health and Family Welfare. Late detection is responsible for poor quality of life (QOL), and it is the leading cause of death. In metropolitan regions, one in every 22 women will have breast cancer over their lifetime; but in rural areas, one in every 60 women will develop breast cancer as per estimates. Aim and objective: This paper aims to describe the various AI based breast screening technologies which are used in breast cancer screening in India. Methodology: The literature search was done using "Pub Med," "Google scholar," and "Scopus" databases for the key terms "technology," "cancer research," "artificial intelligence," "mammography", "breast cancer," "cancer," and/or "neoplasia in breast." All the relevant articles were included to support this mini review. Results: We found that emerging artificial intelligent technologies namely "Niramai", "iBreastExam," "MammoAssist" are emerging as an hope for early detection by screening in resource poor settings, in turn, which can improve the QOL among breast cancer patients.

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