Ibrutinib: from bench side to clinical implications

Abstract

The activation of the B cell receptor (BCR) is nowadays known to play a primary role in the etiopathogenesis of a multitude of B cell malignancies, being one of the main factors responsible for the enhanced proliferation and survival of transformed cells. Thanks to the characterization and continuous discovery of the pathways driving B cell proliferation in consequence to BCR activation, it has been possible to develop a small molecule inhibitor specifically antagonizing the Bruton's tyrosine kinase (BTK), an enzyme located in an early strategic position within the whole pathway. Ibrutinib, formerly PCI-32765, is a first in class, potent, specific, irreversible and relatively safe BTK inhibitor, demonstrating so far an impressive efficacy in the treatment of chronic lymphocytic leukemia, diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma (MCL), Waldenström macroglobulinemia and multiple myeloma. This review will summarize the most important pharmacological evidences available as of today and will take in consideration the latest findings regarding the mechanism of action of ibrutinib.

Bruton's tyrosine kinase regulates TLR7/8-induced TNF transcription via nuclear factor-κB recruitment

“…Non-receptor tyrosine kinases are attractive targets for therapeutic intervention as small molecule inhibitors are readily synthesised [ 32 ]. Btk inhibitors have demonstrated considerable success in clinical trials, particularly in combating B cell malignancies [ 33 , 34 ] and in the treatment of autoimmune disorders such as lupus and inflammatory arthritis in animal models [ [35] , [36] , [37] ]. Btk inhibition acts not only via reduced B cell development and function, but also on other cell types such macrophages limiting cytokine and chemokine production [ 38 , 39 ].…”

Novel drug targets for personalized precision medicine in relapsed/refractory diffuse large B-cell lymphoma: a comprehensive review

“…In a phase I/II clinical trial study that involved 80 subjects with relapsed or refractory DLBCL, ibrutinib (PCI-32765), a BTK inhibitor, have shown a promising activity of ibrutinib as a single agent in the BCR- subtype of ABC-DLBCL; a 37 % ORR and a 16 % CR in relapsed/refractory DLBCL was reported for patients with the ABC- subtype compared with only 5 % of those with the germinal GCB subtype [ 235 – 238 ]. Thus, ibrutinib efficacy is limited to ABC-DLBCL patients with a constitutively active BCR signaling pathway [ 235 , 239 , 240 ]. Consistent with the cooperation between the BCR and MyD88 pathways observed in vitro , ABC tumors with concomitant BCR and MyD88 mutations responded to ibrutinib frequently [ 235 ].…”

“…However, the highest number of responses occurred in ABC tumors that lacked BCR mutations, as 67 % of ibrutinib responders had wild-type CD79A and CD79B [ 235 ]. Remarkably, ibrutinib does not inhibit the growth and survival of BCR wild-type tumors with MyD88- and/or CARD11 mutations [ 235 , 239 , 240 ] indicating that ibrutinib specifically targets ABC-DLBCL tumors that rely on chronic active BCR signaling [ 235 ].…”

“…As mentioned above, a recent clinical phase II study demonstrated that ibrutinib does not inhibit the growth and survival of BCR wild-type ABC-DLBCL tumors with MyD88 mutations [ 235 , 239 , 240 ]. MyD88 is an initial adapter linker protein in the canonical NF-κB signaling pathway activated by Toll-like receptors (TLRs), including the endosomal TLRs 7, 8, and 9 [ 275 ].…”

Efficient bioreductive production of (S)-N-Boc-3-hydroxypiperidine using ketoreductase ChKRED03

“…It has been approved by the US Food and Drug Administration in 2013 for the treatment of mantle cell lymphoma, in 2014 for the treatment of chronic lymphocytic leukemia, and in January 2015 for the treatment of lymphoplasmacytic lymphoma [11][12][13]. (S)-NBHP as well as other enantiopure hydroxypiperidines are important synthetic synthons in the pharmaceutical industry [14].…”