Mechanism of Action Magnifier – 2016 Desk Reference

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Idelalisib: a Selective Inhibitor of the Delta Isoform of Phosphatidylinositol 3-Kinase

There are 4 isoforms of phosphatidylinositol 3-kinase (PI3K) with distinct functions and expression patterns; among those 4 isoforms, PI3K-alpha and PI3K-beta are ubiquitously expressed and involved in a range of cellular functions.1

Both PI3K-gamma and PI3K-delta are expressed predominantly in normal and malignant hematopoietic cells within the bone marrow.1


PI3K-delta plays an essential, nonredundant role in B-cell signaling.2,3 It is a key driver of proliferation through clonal expansion and supports normal and malignant B-cell survival. In certain B-cell malignancies, over time, malignant cells crowd out healthy blood components.1 PI3K-delta signaling within malignant B cells facilitates their interaction with stromal cells and the nurturing microenvironment of the lymph nodes and bone marrow.4 These interactions promote migration of malignant B cells from the periphery to the lymph nodes and bone marrow, a process known as chemotaxis. Hyperactive chemotaxis, dysregulated apoptosis, and hyperactive adhesion lead to accumulation of malignant B cells within lymphoid tissues, which can contribute to lymph node enlargement.


Idelalisib is an inhibitor of phosphatidylinositol 3-kinase (PI3K-delta), which is expressed in normal and malignant B cells.5 Idelalisib inhibits PI3K-delta and blocks multiple signaling pathways, including B-cell receptor signaling and signaling from the CXCR4 and CXCR5 receptors, which are involved in trafficking and homing of B cells to the lymph nodes and bone marrow.5,6 Idelalisib inhibits malignant B-cell proliferation and inhibits signaling with the microenvironment, disrupting chemotaxis and adhesion, and mobilizing malignant B cells from lymphoid tissues into the peripheral blood.5,7 Blocking PI3K-delta with idelalisib induces apoptosis and reduces malignant B-cell viability.5,7

Through mobilizing malignant B cells to the periphery, idelalisib may reduce lymph node burden.7

Idelalisib is approved for 3 indications5:

  • Relapsed chronic lymphocytic leukemia, in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other comorbidities
  • Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least 2 prior systemic therapies
  • Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least 2 prior systemic therapies.

Accelerated approval was granted for FL and SLL based on overall response rate. Improvement in patient survival or disease-related symptoms has not been established.5


  1. Puri KD, Gold MR. Selective inhibitors of phosphoinositide 3-kinase delta: modulators of B-cell function with potential for treating autoimmune inflammatory diseases and B-cell malignancies. Front Immunol. 2012;3:256.
  2. Jou ST, Carpino N, Takahashi Y, et al. Essential, nonredundant role for the phosphoinositide 3-kinase p110delta in signaling by the B-cell receptor complex. Mol Cell Biol. 2002;22:8580-8591.
  3. Herman SE, Gordon AL, Wagner AJ, et al. Phosphatidylinositol 3-kinase-δ inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood. 2010;116:2078-2088.
  4. Burger JA. Nurture versus nature: the microenvironment in chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2011;2011:96-103.
  5. Zydelig [package insert]. Foster City, CA: Gilead Sciences, Inc; 2014.
  6. Macias-Perez IM, Flinn IW. GS-1101: a delta-specific PI3K inhibitor in chronic lymphocytic leukemia. Curr Hematol Malig Rep. 2013;8:22-27.
  7. Fiorcari S, Brown WS, McIntyre BW, et al. The PI3-kinase delta inhibitor idelalisib (GS-1101) targets integrin-mediated adhesion of chronic lymphocytic leukemia (CLL) cell to endothelial and marrow stromal cells. PLoS One. 2013;8:e83830.
Uncategorized - January 5, 2016

Ibrutinib: an Inhibitor of Bruton’s Tyrosine Kinase

B cells circulate between multiple sites in the body during their normal life cycle, and these B cells rely on cues from the support of microenvironments to promote proper development, maturation, and function.1 Chemotaxis to, and adhesion within, proliferative microenvironments, as well as intracellular prosurvival signaling that promotes growth and [ Read More ]

Uncategorized - January 5, 2016

Lenvatinib: a Receptor Tyrosine Kinase Inhibitor

Lenvatinib (Figure) is an orally administered multiple receptor tyrosine kinase (RTK) inhibitor with a novel binding mode that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors1:VEGFR1 (FLT1)VEGFR2 (KDR)VEGFR3 (FLT4).Lenvatinib also inhibits other RTKs involved in tumor proliferation, including1:Fibroblast growth factor receptors 1, 2, 3, and 4The [ Read More ]