A targeted therapy for protein and lipid kinases in chronic lymphocytic leukemia.

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.