Title:A Targeted Therapy for Protein and Lipid Kinases in Chronic Lymphocytic Leukemia
Volume: 19
Issue: 31
Author(s): P. Robak and T. Robak
Affiliation:
Keywords:
AG013736, AVL-292, axitinib, BAY-61-3606, bafetinib, bosutinib, Btk, C-61, CAL-101, CLL, cyclin-dependent kinases,
dasatinib, flavopiridol, fostamatinib, GDC-0834, ibrutinib, Lyn, multikinase inhibitors, NHL, pazopanib, PP2, PI3K, PCI-32765, PI3K, R406, sorafenib, SU6656, sunitinib, Syk, tyrosine kinase inhibitors, vandetanib, SKI-606, TKI258
Abstract: Protein kinases (PKs) and lipid kinases (LKs) are good choices for targets of signal transduction therapy as these enzymes are
involved in signaling pathways, and are often related to the pathogenesis of lymphoid malignancies. The attractiveness of PKs and LKs
as drug able targets is enhanced by the fact that they are enzymes whose biological activity can be turned off by drugs that block their
catalytic site. In the last few years small molecular kinase inhibitors (KIs) have been synthesized and become available for preclinical
studies and clinical trials. The first KI, introduced into clinical practice in 1998, was imatinib mesylate, which became the first choice
drug in chronic myeloid leukemia. More recently, several KIs have been developed to target the proximal B-cell receptor (BCR) signaling
pathway including spleen tyrosine kinase inhibitor (Fostamatinib) and Bruton’s tyrosine kinase inhibitors (Ibrutinib, AVL-263).
These agents are currently evaluated in early clinical trials in chronic lymphocytic leukemia (CLL) and other diseases. Cyclin-dependent
kinase (Cdk) inhibitors, flavopiridol (alvocidib), BMS-387032 (SNS-032), sunitinib and sorafenib are currently under evaluation in clinical
trials for relapsed/refractory CLL. Multi-tyrosine kinase inhibitors including vandetanib (ZD6474) bosutinib (SKI-606), TKI258
(CHIR-258), pazopanib (GW786034) and axitinib (AG013736) have been also developed for the treatment of lymphoid malignancies.
Phosphatidylinositol 3-kinases (PI3K ) are a family of lipid kinases that mediate signals from cell surface receptors. CAL-101 (GS-1101)
is an oral PI3Kδ-specific inhibitor which has shown preclinical and clinical activity against CLL. This article summarizes recent
achievements in the mechanism of action, pharmacological properties and clinical activity and toxicity of PK and LK inhibitors in CLL.
