Discovery and optimization of a potent and selective indazolamine series of IRAK4 inhibitors

Zhai, Wen-Qiang; Lu, Yongping; Zhu, Ya-Bo; Zhou, Mengguang; Cheng, Ya; Shi, Zhenfeng; Qian, Wen‐Jian; Hu, Tai‐Shan; Chen, Lei

doi:10.1016/j.bmcl.2020.127686

Cited by 4 publications

(2 citation statements)

References 20 publications

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“…[44] Based on the literature findings, there are many of small molecules reported as IRAK1 and IRAK4 inhibitors to be used in cancer therapy in the literature. [45,46] For instance, a macrocyclic compound pacritinib (IC 50 6 nM and 177 nM for IRAK1 and IRAK4, respectively, was developed. It was reported the inhibition role on AML and breast cancer cells.…”

Section: Ligandsmentioning

confidence: 99%

Nitro Compounds Inhibit Breast Cancer Cell Proliferation, Migration, and Colony Formation: Molecular Docking, Molecular Dynamics Simulations and Pharmacological Properties

Comert Onder,

Sahin,

Davutlar

et al. 2023

ChemistrySelect

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In this study, the concept of combined in vitro and in silico studies were utilized by using some synthesized nitro bearing compounds. The anticancer activities of the studied compounds were performed by using colony formation analysis, cell cytotoxicity, and migration. Nitro group containing two compounds were analyzed using Hoechst staining to indicate the morphological changes on the nuclei of cancer cells under fluorescence microscopy. Scanning electron microscopy (SEM) analysis was performed with N,N‐dibutyl‐nitro‐substituted compound. Nitro containing anticancer agents were shown the inhibition at 1.5 μM and 2 μM concentrations, and nuclear apoptosis was detected. In addition, cell‐to‐cell interaction on MDA‐MB‐231 cells was broken and observed morphologic changes following the treatment with N,N‐dibutyl‐nitro‐substituted compound at the effective doses. In general, the other nitro compounds showed cell cytotoxicity at 5 μM, 10 μM, and 20 μM. Two hits as anticancer agents were determined as potential interleukin‐1 receptor‐associated kinase 1 (IRAK1) and interleukin‐1 receptor‐associated kinase 4 (IRAK4) inhibitor candidates. Molecular docking and molecular dynamics (MD) simulations studies will provide that the binding patterns with specific residues such as Met265, Tyr284 of the IRAK family members, and these will contribute to further in vitro and in vivo studies for targeted breast cancer therapy.

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Section: Ligandsmentioning

confidence: 99%

Nitro Compounds Inhibit Breast Cancer Cell Proliferation, Migration, and Colony Formation: Molecular Docking, Molecular Dynamics Simulations and Pharmacological Properties

Comert Onder,

Sahin,

Davutlar

et al. 2023

ChemistrySelect

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show abstract

“…23 In addition, AstraZeneca has started a safety and tolerability study of AZD6793 (ClinicalTrials.gov Identifier: NCT 05662033). Indazole-based IRAK4 inhibitors have also recently been described by Zhejiang Hisun Pharmceutical Co. Ltd. 24 Finally, Kymera advanced IRAK4 degrader KT-474 to Phase 2 clinical trials for the treatment of atopic dermatitis and hidradenitis suppurativa (ClinicalTrials.gov Identifiers: NCT06058156 and NCT06028230, studies initiated by collaborator Sanofi). Results from the Phase 1 clinical trial (ClinicalTrials.gov Identifier: NCT04772885) were recently published.…”

Section: Introductionmentioning

confidence: 99%

Discovery of IRAK4 Inhibitors BAY1834845 (Zabedosertib) and BAY1830839

Bothe,

Günther,

Nubbemeyer

et al. 2024

J. Med. Chem.

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Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in innate inflammatory processes. Here, we describe the discovery of two clinical candidate IRAK4 inhibitors, BAY1834845 (zabedosertib) and BAY1830839, starting from a high-throughput screening hit derived from Bayer’s compound library. By exploiting binding site features distinct to IRAK4 using an in-house docking model, liabilities of the original hit could surprisingly be overcome to confer both candidates with a unique combination of good potency and selectivity. Favorable DMPK profiles and activity in animal inflammation models led to the selection of these two compounds for clinical development in patients.

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Role for IRAK-4 and p38 in Neutrophil Signaling in Response to Bacterial Lipoproteins from Staphylococcus aureus

Hook,

Matheis,

Kavanaugh

et al. 2024

Inflammation

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Discovery and optimization of a potent and selective indazolamine series of IRAK4 inhibitors

Cited by 4 publications

References 20 publications

Nitro Compounds Inhibit Breast Cancer Cell Proliferation, Migration, and Colony Formation: Molecular Docking, Molecular Dynamics Simulations and Pharmacological Properties

Nitro Compounds Inhibit Breast Cancer Cell Proliferation, Migration, and Colony Formation: Molecular Docking, Molecular Dynamics Simulations and Pharmacological Properties

Discovery of IRAK4 Inhibitors BAY1834845 (Zabedosertib) and BAY1830839

Role for IRAK-4 and p38 in Neutrophil Signaling in Response to Bacterial Lipoproteins from Staphylococcus aureus

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