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Tyrosine Kinase Inhibitors: Targets Other Than FLT3, BCR-ABL, and c-KIT
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Suzanne R. Hayman, Judith E. Karp
The Src family kinase Lyn is expressed by B lymphocytes and myeloid cells, with growth factor-driven overexpression in AML and B-cell malignancies including lymphoma and multiple myeloma cell lines and constitutive activation in CML by the Bcr-Abl fusion protein (reviewed in 77). Furthermore, Lyn may be overexpressed in CML independent of Bcr-Abl activity and may confer imatinib resistance without concomitant Bcr-Abl mutations (79–81). These findings plus the notable conformational similarities between activated Abl and activated Lyn (82,83) have led to the design of dual-specific inhibitors of both Abl and Src for treatment of imatinib-resistant CML that can bind to both the activated and inactivated forms of Abl and Lyn (84–86). At present, the dual inhibitor dasatinib (Sprycel™, BMS-254825, Bristol-Myers Squibb Company, New Jersey, U.S.) has major clinical activity with induction of hematologic and cytogenetic responses in imatinib-resistant chronic phase (87,88), accelerated phase (89), and blast crisis (90), including those with Bcr-Abl mutations conferring imatinib resistance other than the highly resistant T315I (87–90).
Insulin Therapy for Diabetes: Current Scenario and Future Perspectives
Published in Debarshi Kar Mahapatra, Sanjay Kumar Bharti, Medicinal Chemistry with Pharmaceutical Product Development, 2019
Yogesh A. Kulkarni, R. S. Gaud, Mayuresh S. Garud
The buccal delivery provides similar benefits as that of oral insulin. It has the advantage that it bypasses gastrointestinal degradation. It also provides a relatively larger surface area for absorption and hence results in better bioavailability [75]. Oral-lyn™ was developed by Generex Biotechnology (Canada) as a liquid formulation of short acting insulin which is administered using Generex’s metered dosage aerosol applicator (RapidMist™). The phase 1 and phase 2 trials of use of Oral-lyn™ in patients with type 1 and type 2 showed promising results [76]. Now the phase 3 clinical trial is going on. Oral Recosulin® is an another formulation developed by Shreya Life Sciences Pvt. Ltd., India, which is in phase 3 clinical trials.
Protein Phosphorylation
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
The lyn gene was cloned from a human cDNA library and its product was characterized as a membrane-associated protein of 56-kDa and 512 amino acids, termed p56lyn or Lyn, whose sequences are similar to those of the Lck protein.293,294 The lyn gene is expressed in various tissues of the human fetus, with particularly high levels in the liver. The Lyn protein possesses tyrosine kinase activity and is expressed mainly in macrophages/monocytes, platelets and B lymphocytes, but not in granulocytes, erythrocytes, or T lymphocytes. However, human T-cell lines infected with the HTLV-I retrovirus express the protein. Murine cells express two forms of the Lyn kinase that differ in the presence or absence of 21 amino acid residues in the amino-terminal domain.295,296 These two forms are generated by alternative splicing and possess similar functional properties. They are associated with membrane fractions and may interact with the intracellular domain of cell surface receptors. Lyn proteins are autophosphorylated and may function in the phosphorylation of other cellular proteins in IgM-mediated signal transduction.
Efficacy and safety of idelalisib for the treatment of indolent B-cell malignancies
Published in Expert Opinion on Pharmacotherapy, 2020
Piotr Smolewski, Dominika Rydygier
PI3 Ks are heterodimers comprising regulatory (p85) and catalytic (p110) subunits. PI3 K signaling is mediated by the α, β, γ, and δ catalytic isoforms of the p110 subunit of the enzyme, each with unique functions and expression profiles [5,6]. PI3 Kδ is highly expressed in lymphoid cells and plays an important role for the malignant phenotype in CLL [4,7]. P110δ plays a crucial role in mediating the BCR, and hence in the proliferation, migration, adhesion, and survival of CLL. When the antigen is recognized, Lyn promotes the phosphorylation of Igα and Igβ, which activates the spleen tyrosine kinase (Syk). Syk then initiates the formation of a multi-component ‘signalosome,’ including Btk, Akt, PI3 K, and PLCγ2. BCR co-receptor CD19 is significant for PI3 K activation, which recruits and activates PLCγ2, BTK, and AKT. This leads to the activation of the c-Jun N-terminal kinase (JNK), MEK–extracellular signal-regulated kinase (ERK), mechanistic target of rapamycin (mTOR), and (NF-κB) signaling pathways [8]. The PI3 K/AKT/mTOR pathway controls most hallmarks of cancer, including cell cycle, survival, metabolism, motility, and genomic instability [9].
Proteomics-inspired precision medicine for treating and understanding multiple myeloma
Published in Expert Review of Precision Medicine and Drug Development, 2020
Matthew Ho, Giada Bianchi, Kenneth C. Anderson
In order to further characterize the phosphorylation sites on Lyn kinase, Jin et al. employed label-free quantitative proteomics to determine the relative phosphorylation stoichiometry of Lyn kinase in xenograft MM tumor tissue [97]. Lyn is a protein-tyrosine kinase implicated in IL-6 induced MM proliferation [98]. The study found that KMS11 cells lacked Lyn Y194 kinase activity when compared with KMS12 [97]. A recent study applied phosphoproteomics to study differential kinase activity in MM cell lines [99]. Even though both KRAS and NRAS have traditionally been understood to phosphorylate RAF to activate MAPK signaling, the authors reported that cell lines with activating mutations in KRAS vs NRAS had differential phosphorylation of BRAF, ARAF, and CRAF [99]. This study highlights important differences in KRAS and NRAS signaling outputs and biology.
Targeting the B cell receptor pathway in non-Hodgkin lymphoma
Published in Expert Opinion on Investigational Drugs, 2018
Kelly Valla, Christopher R. Flowers, Jean L. Koff
Key components of the BCR signaling pathway are depicted in Figure 1. Binding of antigen to extracellular BCR results in phosphorylation of highly conserved immunoreceptor tyrosine-based activation motifs (ITAMs) within CD79a and CD79b, which then act as docking sites for additional adaptor molecules and kinases [5]. The three SRC-family kinases LYN, FYN, and B lymphocyte kinase (BLNK) are essential for downstream survival signal propagation early in B cell development, with some functional redundancy between them [6]. LYN directly phosphorylates spleen tyrosine kinase (SYK) to continue signal propagation via Bruton’s tyrosine kinase (BTK), and simultaneously activates phosphatases that inhibit BCR signal transduction, thus serving a dual role by both transmitting and checking BCR signaling [7]. Tonic BCR signaling refers to the BCR-dependent process observed in normal B cells that does not require antigen binding but is mediated by SYK activation of the pro-survival phosphatidylinositol 3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway [8]. Thus, SYK is also activated through autophosphorylation when bound directly to the phosphorylated ITAMs of CD79a/b, at which point it amplifies the BCR signal by promoting further ITAM phosphorylation and activating downstream signaling cascades, including those mediated by PI3K [9].