Discovery of Selective Irreversible Inhibitors for Bruton’s Tyrosine Kinase

Pan, Zhengying; Scheerens, Heleen; Li, Shyr‐Jiann; Schultz, Brian E.; Sprengeler, Paul A.; Burrill, Leland C.; Mendonca, Rohan; Sweeney, M. D.; Scott, Keana C.; Grothaus, Paul G.; Jeffery, Douglas A.; Spoerke, Jill M.; Honigberg, Lee; Young, Peter R.; Dalrymple, Stacie A.; Palmer, James T.

doi:10.1002/cmdc.200600221

Cited by 596 publications

(550 citation statements)

References 39 publications

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“…The use of irreversible inhibitors has previously been shown to be a viable method to achieve potent and selective inhibition of kinase enzymes (22,23). We previously reported the discovery and characterization of a series of Btk-selective irreversible inhibitors that bind covalently to a noncatalytic Cys (Cys-481) residue in Btk (17). Structural alignments revealed that only 10 kinases have a Cys at this position (17), representing a significant selectivity filter.…”

Section: Discussionmentioning

confidence: 99%

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The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy

Honigberg

Smith

Sirisawad

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Activation of the B-cell antigen receptor (BCR) signaling pathway contributes to the initiation and maintenance of B-cell malignancies and autoimmune diseases. The Bruton tyrosine kinase (Btk) is specifically required for BCR signaling as demonstrated by human and mouse mutations that disrupt Btk function and prevent B-cell maturation at steps that require a functional BCR pathway. Herein we describe a selective and irreversible Btk inhibitor, PCI-32765, that is currently under clinical development in patients with B-cell nonHodgkin lymphoma. We have used this inhibitor to investigate the biologic effects of Btk inhibition on mature B-cell function and the progression of B cell-associated diseases in vivo. PCI-32765 blocked BCR signaling in human peripheral B cells at concentrations that did not affect T cell receptor signaling. In mice with collagen-induced arthritis, orally administered PCI-32765 reduced the level of circulating autoantibodies and completely suppressed disease. PCI-32765 also inhibited autoantibody production and the development of kidney disease in the MRL-Fas(lpr) lupus model. Occupancy of the Btk active site by PCI-32765 was monitored in vitro and in vivo using a fluorescent affinity probe for Btk. Active site occupancy of Btk was tightly correlated with the blockade of BCR signaling and in vivo efficacy. Finally, PCI-32765 induced objective clinical responses in dogs with spontaneous B-cell non-Hodgkin lymphoma. These findings support Btk inhibition as a therapeutic approach for the treatment of human diseases associated with activation of the BCR pathway.lymphoma | X-linked agammaglobulinemia

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Section: Discussionmentioning

confidence: 99%

“…We have previously described the synthesis of a series of Btk inhibitors that bind covalently to a cysteine residue (Cys-481) in the active site leading to potent and irreversible inhibition of Btk enzymatic activity (17). One of these compounds, PCI-32765 ( Fig.…”

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confidence: 99%

The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy

Honigberg

Smith

Sirisawad

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…15 Visual analysis of the kinases identified as having one or more cysteines in the active site based on work by Gray and coworkers 22 led to the merging of four groups into a single one (Table I). Furthermore, for Group 3F, which contains EGFR and BTK that are being targeted with covalent inhibitors, 26,27 we identified another kinase that based on structural overlays should be a member of this group. To the best of our knowledge, MAP2K7 has not been identified as being a member of this group until now.…”

Section: Discussionmentioning

confidence: 99%

An enriched structural kinase database to enable kinome‐wide structure‐based analyses and drug discovery

et al. 2010

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The development of a kinase structural database, the kinase knowledge base (KKB), is described. It covers all human kinase domain structures that have been deposited in the Protein Data Bank. All structures are renumbered using a common scheme, which enables efficient crosscomparisons and multiple queries of interest to the kinase field. The common numbering scheme is also used to automatically annotate conserved residues and motifs, and conformationally classify the structures based on the DFG-loop and Helix C. Analyses of residue conservation in the ATP binding site using the full human-kinome-sequence alignment lead to the identification of a conserved hydrogen bond between the hinge region backbone and a glycine in the specificity surface. Furthermore, 90% of kinases are found to have at least one stabilizing interaction for the hinge region, which has not been described before.

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“…Ibrutinib inactivates BTK by binding covalently to Cysteine 481 in the ATP‐binding site in an irreversible manner 7. This active site occupancy inhibits the subsequent phosphorylation of BTK, phospholipase C γ 2 (PLC γ 2), AKT and ERK and abolishes the BCR signalling downstream of BTK both in vitro and in vivo 8.…”

Section: Introductionmentioning

confidence: 99%

Targets for Ibrutinib Beyond B Cell Malignancies

et al. 2015

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Ibrutinib (Imbruvica™) is an irreversible, potent inhibitor of Bruton's tyrosine kinase (BTK). Over the last few years, ibrutinib has developed from a promising drug candidate to being approved by FDA for the treatment of three B cell malignancies, a truly remarkable feat. Few, if any medicines are monospecific and ibrutinib is no exception; already during ibrutinib's initial characterization, it was found that it could bind also to other kinases. In this review, we discuss the implications of such interactions, which go beyond the selective effect on BTK in B cell malignancies. In certain cases, the outcome of ibrutinib treatment likely results from the combined inhibition of BTK and other kinases, causing additive or synergistic, effects. Conversely, there are also examples when the clinical outcome seems unrelated to inhibition of BTK. Thus, more specifically, adverse effects such as enhanced bleeding or arrhythmias could potentially be explained by different interactions. We also predict that during long‐term treatment bone homoeostasis might be affected due to the inhibition of osteoclasts. Moreover, the binding of ibrutinib to molecular targets other than BTK or effects on cells other than B cell‐derived malignancies could be beneficial and result in new indications for clinical applications.

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Discovery of Selective Irreversible Inhibitors for Bruton’s Tyrosine Kinase

Cited by 596 publications

References 39 publications

The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy

The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy

An enriched structural kinase database to enable kinome‐wide structure‐based analyses and drug discovery

Targets for Ibrutinib Beyond B Cell Malignancies

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