Small molecule approaches to treat autoimmune and inflammatory diseases (Part I): Kinase inhibitors

Wu, Jun; Ding, Xiao; Shen, Hong C.; Zou, Ge

doi:10.1016/j.bmcl.2021.127862

Cited by 18 publications

(9 citation statements)

References 122 publications

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“…BTKi are small-molecule agents. Small molecules have several advantages for biological modulation, compared to large molecules, such as oral dosage, intracellular targeting, and lower manufacturing costs [67]. For MS, the size of these molecules may be another advantage in terms of their ability to cross the BBB, as reported with some inhibitors.…”

Section: Btk Inhibitorsmentioning

confidence: 99%

Bruton’s Tyrosine Kinase Inhibitors: A New Generation of Promising Agents for Multiple Sclerosis Therapy

García‐Merino

2021

Cells

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B cells play a central role in the pathogenesis of multiple sclerosis (MS), as demonstrated through the success of various B cell-depleting monoclonal antibodies. Bruton’s tyrosine kinase (BTK) is a critical molecule in intracellular signaling from the receptor of B cells and receptors expressed in the cells of the innate immune system. BTK inhibitors may be a non-cell-depleting alternative to B cell modulation. In this review, the structure, signaling, and roles of BTK are reviewed among the different inhibitors assayed in animal models of MS and clinical trials.

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Section: Btk Inhibitorsmentioning

confidence: 99%

Bruton’s Tyrosine Kinase Inhibitors: A New Generation of Promising Agents for Multiple Sclerosis Therapy

García‐Merino

2021

Cells

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“…Non-covalent inhibitors with the complementary structural features provided in Figure 10 A portray excellent BTK inhibition and fewer side effects [ 84 , 90 ]. In-vitro and in-vivo side effects of non-covalent inhibitors decreased when functional groups engaging H3 and H2 clefts were optimized, such that H3 binders are highly lipophilic bicyclic/tricyclic planar rings and H2 binders are less lipophilic medium-size rings [ 91 ]. The H3 cleft of BTK is versatile in accommodating binders like bulky, lipophilic t-butyl-oxadiazole, t-butyl-triazole, isopropyl-oxo-azetanyl, trifluoromethyl pyridyl, and t-butyl-pthalazinyl moieties ( Figure 10 B).…”

Section: Structural Complementarity Of Btk and Its Inhibitorsmentioning

confidence: 99%

Structural Complementarity of Bruton’s Tyrosine Kinase and Its Inhibitors for Implication in B-Cell Malignancies and Autoimmune Diseases

et al. 2023

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Bruton’s tyrosine kinase (BTK) is a critical component in B-cell receptor (BCR) signaling and is also expressed in haematogenic and innate immune cells. Inhibition of BTK hyperactivity is implicated in B-cell malignancies and autoimmune diseases. This review derives the structural complementarity of the BTK-kinase domain and its inhibitors from recent three-dimensional structures of inhibitor-bound BTK in the protein data bank (PDB). Additionally, this review analyzes BTK-mediated effector responses of B-cell development and antibody production. Covalent inhibitors contain an α, β-unsaturated carbonyl moiety that forms a covalent bond with Cys481, stabilizing αC-helix in inactive-out conformation which inhibits Tyr551 autophosphorylation. Asn484, located two carbons far from Cys481, influences the stability of the BTK-transition complex. Non-covalent inhibitors engage the BTK-kinase domain through an induced-fit mechanism independent of Cys481 interaction and bind to Tyr551 in the activation kink resulting in H3 cleft, determining BTK selectivity. Covalent and non-covalent binding to the kinase domain of BTK shall induce conformational changes in other domains; therefore, investigating the whole-length BTK conformation is necessary to comprehend BTK’s autophosphorylation inhibition. Knowledge about the structural complementarity of BTK and its inhibitors supports the optimization of existing drugs and the discovery of drugs for implication in B-cell malignancies and autoimmune diseases.

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“…The following table shows representative compounds tested for IRAK4 inhibition and the biological data obtained from testing representative examples. …”

Section: Important Compound Classesmentioning

confidence: 99%

Novel IRAK4 Inhibitors for Treating Asthma

Sabnis¹

2022

ACS Med. Chem. Lett.

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Small molecule approaches to treat autoimmune and inflammatory diseases (Part I): Kinase inhibitors

Cited by 18 publications

References 122 publications

Bruton’s Tyrosine Kinase Inhibitors: A New Generation of Promising Agents for Multiple Sclerosis Therapy

Bruton’s Tyrosine Kinase Inhibitors: A New Generation of Promising Agents for Multiple Sclerosis Therapy

Structural Complementarity of Bruton’s Tyrosine Kinase and Its Inhibitors for Implication in B-Cell Malignancies and Autoimmune Diseases

Novel IRAK4 Inhibitors for Treating Asthma

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