Discovery and structure-activity relationship of novel diphenylthiazole derivatives as BTK inhibitor with potent activity against B cell lymphoma cell lines

Guo, Xiaofeng; Yang, Dongyan; Fan, Zhijin; Zhang, Nailou; Zhao, Bin; Huang, Chen‐Hung; Wang, Fangjie; Ma, Rongji; Meng, Meng; Deng, Youcai

doi:10.1016/j.ejmech.2019.06.035

Cited by 14 publications

(4 citation statements)

References 30 publications

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“…2e ( GNE-431 ) is a potent, selective, and noncovalent BTK inhibitor with IC 50 of 3.2 nM and 2.5 nM for wild-type BTK and C481S mutants, respectively [ 46 , 47 ]. 2e , unlike covalent inhibitors such as 2b , does not form a covalent bond with CYS481 and potently inhibits 2b -resistant BTK C481S mutant in vitro and in vivo.…”

Section: Indole/azaindole/oxindole-based Approved Atp-competitive Kin...mentioning

confidence: 99%

Approved Small-Molecule ATP-Competitive Kinases Drugs Containing Indole/Azaindole/Oxindole Scaffolds: R&D and Binding Patterns Profiling

Zhang

Gao

et al. 2023

Molecules

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Kinases are among the most important families of biomolecules and play an essential role in the regulation of cell proliferation, apoptosis, metabolism, and other critical physiological processes. The dysregulation and gene mutation of kinases are linked to the occurrence and development of various human diseases, especially cancer. As a result, a growing number of small-molecule drugs based on kinase targets are being successfully developed and approved for the treatment of many diseases. The indole/azaindole/oxindole moieties are important key pharmacophores of many bioactive compounds and are generally used as excellent scaffolds for drug discovery in medicinal chemistry. To date, 30 ATP-competitive kinase inhibitors bearing the indole/azaindole/oxindole scaffold have been approved for the treatment of diseases. Herein, we summarize their research and development (R&D) process and describe their binding models to the ATP-binding sites of the target kinases. Moreover, we discuss the significant role of the indole/azaindole/oxindole skeletons in the interaction of their parent drug and target kinases, providing new medicinal chemistry inspiration and ideas for the subsequent development and optimization of kinase inhibitors.

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Section: Indole/azaindole/oxindole-based Approved Atp-competitive Kin...mentioning

confidence: 99%

Approved Small-Molecule ATP-Competitive Kinases Drugs Containing Indole/Azaindole/Oxindole Scaffolds: R&D and Binding Patterns Profiling

Zhang

Gao

et al. 2023

Molecules

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“…Guo et al designed a series of novel diphenylthiazole analogs as potent inhibitors of BTK (Guo, Yang, et al, 2019). Among these compounds, compound 12 (Figure 5) demonstrated high activity and showed inhibition of the C481S mutant of BTK with an IC 50 value of 0.061 μM.…”

Section: Covalent Inhibitors Of Protein Kinasesmentioning

confidence: 99%

Covalent inhibitors: An ambitious approach for the discovery of newer oncotherapeutics

Cheke,

Kharkar

2023

Drug Development Research

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Covalent inhibitors have been used to treat several diseases for over a century. However, strategic approaches for the rational design of covalent drugs have taken a definitive shape in recent times. Since the first appearance of covalent inhibitors in the late 18th century, the field has grown tremendously and around 30% of marketed drugs are covalent inhibitors especially, for oncology indications. However, the off‐target toxicity and safety concerns can be significant issues related to the covalent drugs. Covalent kinase inhibitor (CKI) targeted oncotherapeutics has advanced dramatically over the last two decades since the discovery of afatinib (Gilotrif®), an EGFR inhibitor. Since then, US FDA has approved 10 CKIs for diverse cancer targets. The present review broadly summarizes the ongoing development in the discovery of newer CKIs from 2016 till the end of 2022. We believe that these efforts will assist the modern medicinal chemist actively working in the field of CKI discovery for varied indications.

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“…In this manner, they designed and synthesized novel compound 49 diphenylthiazole derivatives, most of which resulted in good BTKIs (IC 50 values were in the low micromolar range), and antiproliferative agents on B-lymphoma cell lines, and Ramos and Raji cell lines. Unfortunately, the most active compound, compound 42 (IC 50 = 90 nM) ( Figure 12 ), resulted in less activity than Ibrutinib and CGI-1746 [ 114 ].…”

Section: Recent Advances In Btkismentioning

confidence: 99%

The Development of BTK Inhibitors: A Five-Year Update

et al. 2021

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Bruton’s tyrosine kinase (BTK) represented, in the past ten years, an important target for the development of new therapeutic agents that could be useful for cancer and autoimmune disorders. To date, five compounds, able to block BTK in an irreversible manner, have been launched in the market, whereas many reversible BTK inhibitors (BTKIs), with reduced side effects that are more useful for long-term administration in autoimmune disorders, are under clinical investigation. Despite the presence in the literature of many articles and reviews, studies on BTK function and BTKIs are of great interest for pharmaceutical companies as well as academia. This review is focused on compounds that have appeared in the literature from 2017 that are able to block BTK in an irreversible or reversible manner; also, new promising tunable irreversible inhibitors, as well as PROTAC molecules, have been reported. This summary could improve the knowledge of the chemical diversity of BTKIs and provide information for future studies, particularly from the medicinal chemistry point of view. Data reported here are collected from different databases (Scifinder, Web of Science, Scopus, Google Scholar, and Pubmed) using “BTK” and “BTK inhibitors” as keywords.

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Discovery and structure-activity relationship of novel diphenylthiazole derivatives as BTK inhibitor with potent activity against B cell lymphoma cell lines

Cited by 14 publications

References 30 publications

Approved Small-Molecule ATP-Competitive Kinases Drugs Containing Indole/Azaindole/Oxindole Scaffolds: R&D and Binding Patterns Profiling

Approved Small-Molecule ATP-Competitive Kinases Drugs Containing Indole/Azaindole/Oxindole Scaffolds: R&D and Binding Patterns Profiling

Covalent inhibitors: An ambitious approach for the discovery of newer oncotherapeutics

The Development of BTK Inhibitors: A Five-Year Update

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