Medicinal Chemistry Research, Год журнала: 2024, Номер 33(9), С. 1611 - 1624
Опубликована: Июль 10, 2024
Язык: Английский
Pharmaceuticals, Год журнала: 2024, Номер 17(5), С. 620 - 620
Опубликована: Май 10, 2024
Histone deacetylases (HDACs) are crucial in gene transcription, removing acetyl groups from histones. They also influence the deacetylation of non-histone proteins, contributing to regulation various biological processes. Thus, HDACs play pivotal roles diseases, including cancer, neurodegenerative disorders, and inflammatory conditions, highlighting their potential as therapeutic targets. This paper reviews structure function four classes human HDACs. While HDAC inhibitors currently available for treating hematological malignancies, numerous others undergoing clinical trials. However, non-selective toxicity necessitates ongoing research into safer more efficient class-selective or isoform-selective inhibitors. Computational methods have aided discovery with desired potency and/or selectivity. These include ligand-based approaches, such scaffold hopping, pharmacophore modeling, three-dimensional quantitative structure–activity relationships, structure-based virtual screening (molecular docking). Moreover, recent developments field molecular dynamics simulations, combined Poisson–Boltzmann/molecular mechanics generalized Born surface area techniques, improved prediction ligand binding affinity. In this review, we delve ways which these contributed designing identifying
Язык: Английский
Процитировано
14
Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(1), С. 38 - 64
Опубликована: Янв. 2, 2024
Proviral integration sitea for Moloney-murine leukemia virus (PIM) kinases are a family of highly conserved serine/tyrosine consisting three members, PIM-1, PIM-2, and PIM-3. These regulate wide range substrates through phosphorylation affect key cellular processes such as transcription, translation, proliferation, apoptosis, energy metabolism. Several PIM inhibitors currently undergoing clinical trials, phase I trial Uzanserti (5) the treatment relapsed diffuse large B-cell lymphoma that has been completed. The current focus encompasses structural biological characterization PIM, ongoing research progress on small-molecule evaluation analysis persisting challenges in this field. Additionally, design discovery targeting recent years have explored, with particular emphasis medicinal chemistry, aiming to provide valuable insights future development inhibitors.
Язык: Английский
Процитировано
12
RSC Advances, Год журнала: 2025, Номер 15(5), С. 3756 - 3828
Опубликована: Янв. 1, 2025
Pyrazolo[1,5- a ]pyrimidines are notable class of heterocyclic compounds with potent protein kinase inhibitor (PKI) activity, playing critical role in targeted cancer therapy.
Язык: Английский
Процитировано
1
European Journal of Medicinal Chemistry, Год журнала: 2023, Номер 259, С. 115658 - 115658
Опубликована: Июль 17, 2023
Язык: Английский
Процитировано
16
Nature Immunology, Год журнала: 2024, Номер 25(2), С. 282 - 293
Опубликована: Янв. 3, 2024
Язык: Английский
Процитировано
6
Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(18), С. 15968 - 15995
Опубликована: Сен. 11, 2024
Heat shock protein 90 (HSP90), a highly conserved member of the heat family, regulates various proteins and signaling pathways involved in cancer, making it promising target for cancer therapy. Traditional HSP90 inhibitors have demonstrated significant antitumor potential preclinical trials, with over 20 compounds advancing to clinical trials showing results. However, limited efficacy shared toxicity these restrict their further use. Encouragingly, developing novel using conventional medicinal chemistry approaches─such as selective inhibitors, dual protein-protein interaction proteolysis-targeting chimeras─is expected address challenges. Notably, inhibitor TAS-116 has already been successfully marketed. In this Perspective, we summarize structure, biological functions, roles analyze status highlight latest advancements strategies, offering insights into future development.
Язык: Английский
Процитировано
6
Biological Chemistry, Год журнала: 2025, Номер unknown
Опубликована: Март 21, 2025
Abstract Protein kinase CK2 is a promising therapeutic target, especially in oncology. Over the years, various inhibitors have been developed, with polyhalogenated scaffolds emerging as particularly effective class. Halogens like bromine and chlorine enhance inhibitor stability by forming additional interactions within ATP pocket. Among halogenated scaffolds, benzotriazole benzimidazole led to potent molecules such 4,5,6,7-tetrabromo-1 H -benzotriazole (IC 50 = 300 nM) 4,5,6,7-tetrabromo-2-(dimethylamino)benzimidazole 140 nM). Modifications, including 4,5,6-tribromo-7-ethyl-1 160 nM), further improved activity. Changing while retaining halogens has enabled design of new inhibitors. Flavonols, dibenzofuranones, indeno[1,2- b ]indole scaffold are key examples. Halogenation reference molecule 5-isopropyl-5,6,7,8-tetrahydroindeno[1,2- ]indole-9,10-dione ( 4b , IC 360 significantly boosted potency. The study focused on introducing four halogens, yielding compound 1,2,3,4-tetrabromo-5-isopropyl-5,6,7,8-tetrahydroindeno[1,2- MC11 ), an 16 nM. Co-crystallography revealed how atoms binding, demonstrated strong cellulo activity, against leukemic cell lines IPC-Bcl2.
Язык: Английский
Процитировано
0
Bioorganic Chemistry, Год журнала: 2023, Номер 140, С. 106831 - 106831
Опубликована: Сен. 3, 2023
Язык: Английский
Процитировано
12
Cancers, Год журнала: 2023, Номер 15(14), С. 3711 - 3711
Опубликована: Июль 21, 2023
The protein kinase CK2 (also known as casein 2) is one of the main contributors to human phosphoproteome. It regarded a possible therapeutic strategy in several malignant diseases, including acute myeloid leukemia (AML), which an aggressive bone marrow malignancy. important regulator intracellular signaling AML cells, especially PI3K-Akt, Jak-Stat, NFκB, Wnt, and DNA repair signaling. High levels cells at first time diagnosis are associated with decreased survival (i.e., increased risk chemoresistant relapse) for patients receiving intensive potentially curative antileukemic therapy. However, it not whether these high can be used independent prognostic biomarker because this has been investigated multivariate analyses. Several inhibitors have developed, but CX-4945/silmitasertib best characterized. This drug antiproliferative proapoptotic effects primary cells. preliminary results from studies silmitasertib treatment other malignancies suggest that gastrointestinal toxicities relatively common. clinical available. Taken together, available experimental evidence suggests use inhibition should further investigated.
Язык: Английский
Процитировано
11
European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 268, С. 116291 - 116291
Опубликована: Фев. 27, 2024
Язык: Английский
Процитировано
4