Ibrutinib inhibition of Bruton protein-tyrosine …

1 Pharmacological Research 113 (2016) 395 408 Contents lists available atScienceDirectPharmacological Researchjournal ReviewIbrutinib inhibition of Bruton protein - tyrosine kinase (BTK) in thetreatment of B cell neoplasmsRobert Roskoski Ridge Institute for Medical Research, 3754 Brevard Road, Suite 116, Box 19, Horse Shoe, NC 28742-8814, United Statesa r t i c l e i n f oArticle history:Received 11 September 2016 Accepted 12 September 2016 Available online 15 September 2016 Chemical compounds studied in this article:Bendamustine (PubMed CID: 65628)Carfilzomib (PubMed CID: 11556711)Dasatinib (PubMed CID: 3062316)Fludarabine (PubMed CID: 657237) Ibrutinib (PubMed CID: 24821094)Idelalisib (PubMed CID: 11625818)Palbociclib (PubMed CID: 5330286)Pomalidomide (PubMed CID: 134780)Venetoclax (PubMed CID: 49846579)Vistusertib (PubMed CID: 44200550)Keywords:Catalytic spineChronic lymphocytic leukemiaK/E/D/DMantle cell lymphomaWaldenstr m macroglobulinemiaa b s t r a c tThe Bruton non-receptor protein - tyrosine kinase (BTK), a deficiency of which leads to X-linked agam-maglobulinemia, plays a central role in B cell antigen receptor signaling .

2 Owing to the exclusivity of thisenzyme in B cells, the acronym could represent B cell tyrosine kinase. BTK is activated by the Lyn andSYK protein kinases following activation of the B cell receptor. BTK in turn catalyzes the phosphoryla-tion and activation of phospholipase C 2 leading to the downstream activation of the Ras/RAF/MEK/ERKpathway and the NF- B pathways. Both pathways participate in the maturation of antibody-producingB cells. The BTK domains include a PH (pleckstrin homology) domain that interacts with membrane-associated phosphatidyl inositol trisphosphate, a TH (TEC homology) domain, which is followed by anSH3, SH2, and finally a protein kinase domain. Dysregulation of B cell receptor signaling occurs in sev-eral B cell neoplasms including mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenstr mmacroglobulinemia. Ibrutinib is FDA-approved as first-line or second line treatment for these drug binds tightly in the ATP-binding pocket of BTK making salt bridges with residues within thehinge that connects the two lobes of the enzyme; then its unsaturated acrylamide group forms a cova-lent bond with BTK cysteine 481 to form an inactive adduct.

3 In addition to the treatment of various B celllymphomas, Ibrutinib is under clinical trials for the treatment of numerous solid tumors owing to therole of tumor-promoting inflammation in the pathogenesis of neoplastic diseases. 2016 Published by Elsevier The role of Bruton protein - tyrosine kinase in B cell antigen receptor signaling .. 3962. Biochemistry of the Bruton protein - tyrosine kinase .. Architecture of BTK .. Primary structure of BTK.. The secondary and tertiary structure of BTK and the K/E/D/D motif.. Active and inactive BTK hydrophobic spines .. Interconversion of inactive and active BTK .. 3993. FDA-approved Ibrutinib disease targets .. Mantle cell lymphoma (MCL) .. Chronic lymphocytic leukemia (CLL) .. Waldenstr m macroglobulinemia (WM) .. 4044. Selected Ibrutinib clinical trials .. 404 Abbreviations: AS, activation segment; CLL, chronic lymphocytic leukemia; CS or C-spine, catalytic spine; CL, catalytic loop; H or , hydrophobic; IP3, inositol 1,4,5trisphosphate; IP6, inositol 1,2,3,4,5,6 hexakisphosphate; MCL, mantle cell lymphoma; MW, molecular weight; NSCLC, non-small cell lung cancer; PKA, protein kinase A;PIP2, phosphatidyl inositol 4,5 bisphosphate; PIP3, phosphatidyl inositol 3,4,5 trisphosphate; RA, rheumatoid arthritis; RS or R-spine, regulatory spine; Sh1, shell residue 1;WM, Waldenstr m address: 2016 Published by Elsevier R.

4 Roskoski Jr. / Pharmacological Research 113 (2016) 395 4085. Binding of Ibrutinib and dasatinib to BTK .. 4056. Covalent protein kinase inhibitors .. 4067. Epilogue..406 Conflict of interest..407 Acknowledgement .. 407 References .. 4071. The role of Bruton protein - tyrosine kinase in B cellantigen receptor signalingThe Bruton kinase was originally identified in 1993 as a non-receptor protein - tyrosine kinase that is defective in X-linkedagammaglobulinemia [1 4]. B lymphocytes and immunoglobulinsare almost completely nonexistent in affected males with this rareaffliction making them susceptible to infections, but they respondfavorably to parenteral injections of human immunoglobulins [5].Patients with this disorder have no significant alterations in cellsother than B cells, and this observation is consonant with therestriction of clinical features to B cell immunity. Moreover, theX-linked immunodeficiency (XID) phenotype in the CBA/N strainof mice results from an R28C mutation near the amino-terminus ofBTK, which is outside of the enzyme protein kinase domain [4].

5 During development, each B cell recombines immunoglobulinvariable (V), diversity (D), and junction genes (J) thereby form-ing a unique sequence that establishes the antigen-binding site ofthe B cell receptor [6]. B cell receptor signaling requires a networkof protein kinases and adaptors that mediate antigen stimulationto intracellular responses. The B cell receptor complex consistsof the receptor bound to a disulfide-linked Ig -Ig antigen stimulation of the receptor, the Src family kinase Lyncatalyzes the phosphorylation of pairs of tyrosine residues in Ig -Ig immunoreceptor tyrosine -based activation motifs (ITAMs) thuscreating a docking site for the two SH2 domains of SYK (spleentyrosine kinase) [7]. SYK attracts and activates PI3 kinase- , whichcatalyzes the conversion of membrane-associated phosphatidylinositol 4,5 bis-phosphate (PIP2) to phosphatidyl inositol 3,4,5-trisphosphate (PIP3). The amino-terminal PH lipid-interactionmodule of BTK is attracted to PIP3thereby allowing SYK and Lynto catalyze the trans-phosphorylation of BTK at Tyr551 within theactivation segment that results in enzyme activation.

6 The attrac-tion of BTK dimers to PIP3molecules within the membrane canalso result in activation segment trans-autophosphorylation catalyzes the phosphorylation of PLC 2 at residues Tyr753and Tyr759 resulting in an increase in phospholipase activity[8]. PLC 2 catalyzes the hydrolysis of PIP2to generate inositoltrisphosphate (IP3) and diacylglycerol (DAG). IP3releases Ca2+from intracellular stores, which activates PLC 2. In turn, DAGand Ca2+activate PKC , which leads to the activation of theRas/RAF/MEK/ERK signaling module that promotes cell growth andproliferation [9 12]. PKC also activates the NF- B pathway bymeans of a scaffold complex that includes CARD11 (caspase recruit-ment domain-containing protein 11), BCL10 (B cell lymphomaprotein 10), and MALT1 (mucosa-associated lymphoid tissue lym-phoma translocation protein 1) (Fig. 1). I B (inhibitor of kappaB- ) inactivates the NF- B transcription factor by masking thenuclear localization signals of NF- B and keeps it sequestered inan inactive state in the cytoplasm.

7 The inhibitor of B kinase (IKK)catalyzes the phosphorylation of the inhibitory I B , which resultsin its (i) dissociation from NF- B, (ii) ubiquitylation, and (iii) pro-teosomal degradation. The unsequestered NF- B translocates intothe nucleus and activates the expression of more than 150 B is a rapidly acting transcription factor that regulates, interalia, cell survival and cytokine production. Additionally, BTK playsan essential role in the chemokine-mediated homing and adhesionof B cells [13]. As a result of BTK inhibition , B cells may be releasedfrom lymphatic tissue into the blood stream, which is commonlyobserved after treatment with Ibrutinib . Besides its role in B cellantigen receptor signaling , BTK also participates in chemokine andToll-like receptor signal transduction [8].In contrast to the oncogenic activating B-RAF V600E mutationin melanoma and the JAK2 V617F mutation in polycythemia veraas well as numerous activating EGFR/ERBB1 mutations in lung can-cer, no activating mutations in BTK have been described in B cellneoplasms [8,9,12].

8 However, it appears that there is a chronicincrease in B cell antigen receptor signaling in various B cell lym-phomas [8]. Many lymphomas maintain B cell receptor signaling byresponding to foreign or self antigens within the tumor microen-vironment; the preponderance of evidence favors the interactionwith self antigens. B cell proliferation that is driven by such anti-gens is essential for the pathogenesis of these afflictions. Moreover,sustained activity of the B cell receptor pathway is required forlymphocyte Biochemistry of the Bruton protein - tyrosine Architecture of BTKBTK belongs to the TEC family of non-receptor protein -tyrosinekinases including BTK, TEC, ITK (inducible T cell kinase), TXK(also known as RLK, resting lymphocyte kinase), and BMX (bonemarrow-expressed kinase) [14]. BTK contains a short amino-terminal pleckstrin homology (PH) domain, a TEC homology (TH)domain, followed by an SH3, SH2, and carboxyterminal proteinkinase domain (Fig. 2A), which is an architecture shared with theother members of TEC family of protein kinases.

9 This architectureis similar to that of the Src family of protein kinases except thatthey lack the PH and TH domains, but they contain a myristoylatedamino-terminal domain, which is responsible for their binding tothe plasma membrane (Fig. 2B) [15,16]. In contrast, the PH domainof the TEC family is attracted to membrane-associated PIP3, whichis responsible for their membrane-localization. Src possesses a car-boxyterminal tail inhibitory protein - tyrosine phosphorylation sitethat binds intramolecularly with its SH2 domain to form an autoin-hibited enzyme. BTK lacks this phosphorylation site indicating thatthe mechanism for the interconversion of active and inactive formsof BTK differs in detail from that of Src as described in Section catalyzes the phosphorylation of protein - tyrosine residuesin substrates such as PLC 2. Members of the PLC 2 family pos-sess an intricate architecture consisting of an N-terminal pleckstrinhomology domain, four EF hands, an X domain, a second PH domaincontaining two SH2 and one SH3 domain followed by a Y domain, aC2 domain, and C-terminal domain; the catalytic residues residein the split X and Y segments [17].

10 The PLC 2 phosphorylationsites (Y753, Y759) encompass the residues occur between the second PLC 2 SH2 domain andthe following SH3 domain. The stoichiometry of the protein kinasereaction is given by the following chemical equation:MgATP1 + protein O : H protein O : PO32 + MgADP + H+R. Roskoski Jr. / Pharmacological Research 113 (2016) 395 408 397 Fig. 1. Role of the Bruton protein - tyrosine kinase in B cell receptor signaling . Thedashed arrows indicate that several steps may be that the phosphorylium ion (PO32 ) is transferred fromATP to the protein substrate and not the phosphate (OPO32 ) Primary structure of BTKH anks and Hunter analyzed the sequences of about 60 proteinkinases from various families and divided the primary structuresinto 12 domains (I-VIA,VIB-XI) [18]. The catalytic domains ofprotein kinases contain 250 300 amino acid residues. DomainI of BTK is called the glycine-rich loop (GRL) and contains aGxGx G signature (409 GTGQFG414), where refers to a hydropho-bic residue, and in the case of BTK the hydrophobic residue isphenylalanine.