Selective inhibitors of phosphoinositide 3-kinase delta: modulators of B-cell function with potential for treating autoimmune inflammatory diseases and B-cell malignancies

Abstract

The delta isoform of the p110 catalytic subunit (p110δ) of phosphoinositide 3-kinase is expressed primarily in hematopoietic cells and plays an essential role in B-cell development and function. Studies employing mice lacking a functional p110δ protein, as well as the use of highly-selective chemical inhibitors of p110δ, have revealed that signaling via p110δ-containing PI3K complexes (PI3Kδ) is critical for B-cell survival, migration, and activation, functioning downstream of key receptors on B cells including the B-cell antigen receptor, chemokine receptors, pro-survival receptors such as BAFF-R and the IL-4 receptor, and co-stimulatory receptors such as CD40 and Toll-like receptors (TLRs). Similarly, this PI3K isoform plays a key role in the survival, proliferation, and dissemination of B-cell lymphomas. Herein we summarize studies showing that these processes can be inhibited in vitro and in vivo by small molecule inhibitors of p110δ enzymatic activity, and that these p110δ inhibitors have shown efficacy in clinical trials for the treatment of several types of B-cell malignancies including chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). PI3Kδ also plays a critical role in the activation, proliferation, and tissue homing of self-reactive B cells that contribute to autoimmune diseases, in particular innate-like B-cell populations such as marginal zone (MZ) B cells and B-1 cells that have been strongly linked to autoimmunity. We discuss the potential utility of p110δ inhibitors, either alone or in combination with B-cell depletion, for treating autoimmune diseases such as lupus, rheumatoid arthritis, and type 1 diabetes. Because PI3Kδ plays a major role in both B-cell-mediated autoimmune inflammation and B-cell malignancies, PI3Kδ inhibitors may represent a promising therapeutic approach for treating these diseases.

Keywords: CAL-101; GS-1101; IC87114; autoimmunity; leukemia; non-Hodgkin lymphoma; p110delta; phosphoinositide 3-kinase.

Figure 1

PI3Kδ is a central signaling enzyme that mediates the effects of multiple receptors on B cells. PI3Kδ signaling is important for B-cell survival, migration, and activation, functioning downstream of the B-cell antigen receptor (BCR) and its co-receptor CD19, chemokine receptors (CXCR5), and activating/co-stimulatory receptors such as CD40 and Toll-like receptors (TLRs). Cytokines derived from lymphoid stromal cells (BAFF, IL-6) and T cells (IL-4) that are essential for the expansion and survival of B cells also require PI3Kδ for their actions and bind receptors that activate PI3Kδ. The receptors depicted in this figure use a variety of kinases and adaptor proteins to recruit PI3Kδ to the plasma membrane, where it can produce the lipid second messenger PIP₃. By binding to PH domain-containing proteins, PIP₃ promotes the activation of multiple signaling enzymes including PLCγ 2 and Akt, both of which control key signaling networks. Note that the connecting arrows may represent multiple intermediate signaling reactions.