Design and synthesis of carbazole carboxamides as promising inhibitors of Bruton’s tyrosine kinase (BTK) and Janus kinase 2 (JAK2)

Liu, Qingjie; Batt, Douglas G.; Lippy, Jonathan; Surti, Neha; Tebben, Andrew J.; Muckelbauer, J.K.; Chen, Lin; An, Yongmi; Chang, Chiehying; Pokross, Matt; Yang, Zheng; Wang, Haiqing; Burke, James R.; Carter, Percy H.; Tino, Joseph A.

doi:10.1016/j.bmcl.2015.07.102

Cited by 25 publications

(23 citation statements)

References 19 publications

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“…The selected conformation exhibited a binding energy of −4.22 kcal/mol. The binding pocket of BTK kinase is mainly contributed by residues Leu408, Ala428, Lys430, Met449, Thr474, Glu475, Met477, Ser538, Asp539 and Phe540 [28]. The docked conformation of compound 26 with Btk kinase is shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The recent high-resolution crystal structure of Bruton’s tyrosine kinase was retrieved from the protein data bank (PDB ID: 5BQ0) [28]. The residues from loop region 552–557 were reported missing in crystal structure.…”

Section: Methodsmentioning

confidence: 99%

“…The active site residues of Bruton’s tyrosine kinase were reported in previous studies [24, 25, 28]. The residues around 4 Å of the co-crystallized ligand were considered as the binding site for docking studies.…”

Section: Methodsmentioning

confidence: 99%

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Receptor-guided 3D-QSAR studies, molecular dynamics simulation and free energy calculations of Btk kinase inhibitors

et al. 2017

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BackgroundBruton tyrosine kinase (Btk) plays an important role in B-cell development, differentiation, and signaling. It is also found be in involved in male immunodeficiency disease such as X-linked agammaglobulinemia (XLA). Btk is considered as a potential therapeutic target for treating autoimmune diseases and hematological malignancies.ResultsIn this work, a combined molecular modeling study was performed on a series of thieno [3,2-c] pyridine-4-amine derivatives as Btk inhibitors. Receptor-guided COMFA (q 2 = 0.574, NOC = 3, r 2 = 0.924) and COMSIA (q 2 = 0.646, NOC = 6, r 2 = 0.971) models were generated based on the docked conformation of the most active compound 26. All the developed models were tested for robustness using various validation techniques. Furthermore, a 5-ns molecular dynamics (MD) simulation and binding free energy calculations were carried out to determine the binding modes of the inhibitors and to identify crucial interacting residues. The rationality and stability of molecular docking and 3D-QSAR results were validated by MD simulation. The binding free energies calculated by the MM/PBSA method showed the importance of the van der Waals interaction.ConclusionsA good correlation between the MD results, docking studies, and the contour map analysis were observed. The study has identified the key amino acid residues in Btk binding pocket. The results from this study can provide some insights into the development of potent, novel Btk inhibitors.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-017-0385-5) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Receptor-guided 3D-QSAR studies, molecular dynamics simulation and free energy calculations of Btk kinase inhibitors

et al. 2017

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“…Closely related analogs, on the other hand, gave poor oral exposure in mouse pharmacokinetic study. Aiming to overcome these pharmacokinetic deficiencies, Liu et al designed a series of 4,7‐disubstituted carbazole carboxamide derivatives using a conformation constraining strategy (Figure ). The original flexible N ‐phenylpyridinamine structure was locked by replacement of a tricyclic carbazole ring.…”

Section: Btk Inhibitorsmentioning

confidence: 99%

Targeting Bruton's tyrosine kinase for the treatment of B cell associated malignancies and autoimmune diseases: Preclinical and clinical developments of small molecule inhibitors

Zhang

Liu

et al. 2018

Archiv der Pharmazie

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B cell receptor (BCR) signaling plays a key role in B cell development and function. Aberrant BCR signaling has been confirmed as a central driver for the pathogenesis of various B cell malignancies. Bruton's tyrosine kinase (BTK) is a vital component of BCR signaling and exhibits overexpression in various B cell leukemias and lymphomas. Inhibiting BTK has been proved as an efficient way for B cell malignancy intervention. Remarkable achievements have been made in the pursuit of selective BTK inhibitors, represented by the success of the irreversible BTK inhibitors, ibrutinib and acalabrutinib. Constantly emerging agents exhibiting superior efficacy and safety in preclinical and clinical studies provide promising therapeutics for the treatment of B cell malignancies.

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“…In the past decades, BTK inhibitors have been considered as a therapeutic option for the treatment of B cell malignancies. [13][14][15][16][17][18][19][20][21] Ibrutinib, which is a selective irreversible BTK inhibitor, has been approved by the US Food and Drug Administration (FDA) for the treatment of patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL) and…”

Section: Introductionmentioning

confidence: 99%

Discovery of new BTK inhibitors with B cell suppression activity bearing a 4,6-substituted thieno[3,2-d]pyrimidine scaffold

Zhang

et al. 2017

RSC Adv.

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Design and synthesis of carbazole carboxamides as promising inhibitors of Bruton’s tyrosine kinase (BTK) and Janus kinase 2 (JAK2)

Cited by 25 publications

References 19 publications

Receptor-guided 3D-QSAR studies, molecular dynamics simulation and free energy calculations of Btk kinase inhibitors

Receptor-guided 3D-QSAR studies, molecular dynamics simulation and free energy calculations of Btk kinase inhibitors

Targeting Bruton's tyrosine kinase for the treatment of B cell associated malignancies and autoimmune diseases: Preclinical and clinical developments of small molecule inhibitors

Discovery of new BTK inhibitors with B cell suppression activity bearing a 4,6-substituted thieno[3,2-d]pyrimidine scaffold

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