Development of the Bruton's tyrosine kinase inhibitor ibrutinib for B cell malignancies

Abstract

Ibrutinib is a first-in-class oral covalent inhibitor of Bruton's tyrosine kinase that has demonstrated clinical benefit for many patients with B cell malignancies. Positive results in initial trials led the U.S. Food and Drug Administration to grant ibrutinib three breakthrough therapy designations for mantle cell lymphoma (MCL), del17p chronic lymphocytic leukemia (CLL), and Waldenström's macroglobulinemia (WM). Ibrutinib was approved for these three cancers within 14 months of the original U.S. approval. Additionally, ibrutinib is approved for patient subsets with MCL and/or CLL in >45 other countries. Via a unique mechanism of action, ibrutinib inhibits B cell signaling pathways that regulate the survival, proliferation, adhesion, and homing of cancerous cells. This marks a paradigm shift from the conventional cytotoxic chemotherapy approach to treating B cell malignancies. Ibrutinib continues to be evaluated across a range of B cell malignancies, either as single-agent therapy or in combination with other therapies, and continues to transform the lives of these patients.

Discovery of Potent and Selective Tricyclic Inhibitors of Bruton’s Tyrosine Kinase with Improved Druglike Properties

“…6−14 Of these, the most advanced compound to date is ibrutinib, recently approved for treatment of Mantle Cell Lymphoma (MCL), chronic lymphocytic leukemia (CLL), and Waldenstrom’s macroglobulinemia and under evaluation in additional indications. 15 …”

Specificity of Protein Covalent Modification by the Electrophilic Proteasome Inhibitor Carfilzomib in Human Cells

“…Historically, drug designers have been reluctant to create compounds that act via covalent protein modification, because of concerns about potential toxicity arising from off-target binding of the compound to other cellular proteins. However, recent successes with designed covalent inhibitors such as ibrutinib have renewed interest in this class of molecules (1)(2)(3)(4)(5)(6).…”

Targeting Brutons Tyrosine Kinase in Chronic Lymphocytic Leukemia at the Crossroad between Intrinsic and Extrinsic Pro-survival Signals

“…This finding, together with a decrease in surface CXCR4 levels through the inhibition of CXCR4 phosphorylation at Ser339 by Ibrutinib, results in the rapid leukemic cell redistribution from secondary lymphoid organs to blood [64]. Preclinical studies have shown that Ibrutinib effectively inhibits the proliferation of malignant B lymphocytes and their survival in vivo, as well as cell migration and adhesion to the substrate in vitro [65].…”