Discovery of potent and selective reversible Bruton’s tyrosine kinase inhibitors

Qiu, Hao; Ali, Zahid; Bender, Andrew T.; Caldwell, Richard D.; Chen, Yiying; Fang, Ziming; Gardberg, A.S.; Glaser, Nina; Goettsche, Anja; Goutopoulos, Andreas; Grenningloh, Roland; Hanschke, Bettina; Head, Jared; Johnson, Theresa; Jones, Christopher C.; Jones, Reinaldo; Kulkarni, Shashank; Maurer, Christine K.; Morandi, Federica; Neagu, Constantin; Poetzsch, Sven; Potnick, Justin R.; Schmidt, Ralf; Roe, Katherine; Follis, Ariele Viacava; Wing, Carolyn; Zhu, Xiaohua; Sherer, Brian

doi:10.1016/j.bmc.2021.116163

Cited by 13 publications

(5 citation statements)

References 41 publications

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“…It inhibited only two off-target kinases, FGR (IC 50 = 5.36 µM) and Src (IC 50 = 27.12 µM), and its inhibitory activity was closest to that of BTK. In addition, the compound exhibited favourable pharmacokinetics and showed potent dose-dependent efficacy in a rat CIA model 87 .…”

Section: Oxadiazolementioning

confidence: 96%

Research progress on the synthesis and pharmacology of 1,3,4-oxadiazole and 1,2,4-oxadiazole derivatives: a mini review

Wang

Sun

Jia

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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Oxadiazole is a five-membered heterocyclic compound containing two nitrogen atoms and one oxygen atom. The 1,3,4-oxadiazole and 1,2,4-oxadiazole have favourable physical, chemical, and pharmacokinetic properties, which significantly increase their pharmacological activity via hydrogen bond interactions with biomacromolecules. In recent years, oxadiazole has been demonstrated to be the biologically active unit in a number of compounds. Oxadiazole derivatives exhibit antibacterial, anti-inflammatory, anti-tuberculous, anti-fungal, anti-diabetic and anticancer activities. In this paper, we report a series of compounds containing oxadiazole rings that have been published in the last three years only (2020–2022) as there was no report or their activities described in any article in 2019, which will be useful to scientists in research fields of organic synthesis, medicinal chemistry, and pharmacology.

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Section: Oxadiazolementioning

confidence: 96%

Research progress on the synthesis and pharmacology of 1,3,4-oxadiazole and 1,2,4-oxadiazole derivatives: a mini review

Wang

Sun

Jia

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Development in non-covalent inhibitors’ chemistry and BTK binding was ascertained from PDB structures deposited recently. PDB IDs 7KXQ, 6W07, 7LTZ, 6XE4, and 6X3P were investigated for the structural complementarity between BTK-NCovis [ 84 , 85 , 86 , 87 , 88 ]. Overlay of the fenebrutinib-bound BTK-kinase domain on BTKbound to the recent non-covalent inhibitors in Figure 9 , shows that the currently developed BTK-Ncovi occupy and interact with the kinase domain of BTK.…”

Section: Structural Complementarity Of Btk and Its Inhibitorsmentioning

confidence: 99%

“…Novel BTK-Ncovi have cycloheptyl benzene, azepinyl benzene, imidazopyrazine, phenyl pyrimidine, and dipyridine as core functional scaffolds. Appropriate H3, H2, and H1 binders shall improve potency by enhancing the duration of residence of inhibitors inside the binding clefts [ 85 , 86 , 87 , 88 , 89 , 91 ]. Thus, the BTK-kinase domain provides a complementary binding region for induced-fit docking of non-covalent inhibitors with complementary structures that determines the pharmacodynamic and pharmacokinetic profiles of inhibitors.…”

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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“…4 Bruton's tyrosine kinase (BTK), a member of Tec family kinase, is expressed in B-lineage cells and myeloid cells, and is a key component of BCR signaling pathway, which regulates the survival, activation, proliferation, differentiation and maturation of B cells. [5][6] In BCR signaling pathway, BTK is phosphorylated and activated by SYK and LYN kinases. Activated BTK leads to activation of multiple signaling networks including RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, and nuclear factor kappa B (NF-κB) pathways, which regulate the activation, survival, and proliferation of B cells.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, the non-covalent binding with the target decreases the toxicity and potential risks associated with covalent inhibitors, such as allergic reactions resulting from haptenization of serum proteins by the Michael acceptors. 5,16 Therefore, development of reversible BTK inhibitors has important clinical value and signi cance.…”

Section: Introductionmentioning

confidence: 99%

Design and synthesis of novel pyrazolopyrimidine-based derivatives as reversible BTK inhibitors with potent antiproliferative activity in mantle cell lymphoma

Ran

Zhao

2022

Med Chem Res

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Development of Bruton's tyrosine kinase (BTK) inhibitors is of great value and signi cance in the treatment of B-cell malignancies and autoimmune diseases. Herein, a novel class of pyrazolopyrimidinebased BTK inhibitors were designed and evaluated in mantle cell lymphoma (MCL) cell lines. We demonstrated that target compounds had made great progress in improvement of antiproliferative activity compared to lead compound. Compounds 13c, 13g, 13h, 13l, 13n and 13o demonstrated effectively antiproliferative activity in MCL cells lines with single-digit micromolar potency. Furthermore, compound 13l speci cally disturbed mitochondrial membrane potential and increased reactive oxygen species level in Z138 cells in a dose-dependent manner. 13l induced cell apoptosis through the caspase 3-mediated apoptotic pathway in Z138 cells. Overall, this study provides valuable lead compounds for developing antitumor agents.

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Discovery of potent and selective reversible Bruton’s tyrosine kinase inhibitors

Cited by 13 publications

References 41 publications

Research progress on the synthesis and pharmacology of 1,3,4-oxadiazole and 1,2,4-oxadiazole derivatives: a mini review

Research progress on the synthesis and pharmacology of 1,3,4-oxadiazole and 1,2,4-oxadiazole derivatives: a mini review

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

Design and synthesis of novel pyrazolopyrimidine-based derivatives as reversible BTK inhibitors with potent antiproliferative activity in mantle cell lymphoma

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