We also tested a novel dual p110/ inhibitor, IPI-443 (Table ?(Table1),1), to determine whether p110 inhibition increases the effects beyond blockade of p110 alone. malignancies. p110 inhibitors can suppress autoantibody production in mouse models, but limited clinical trials in human autoimmunity have been performed with PI3K inhibitors to date. Thus, there is a need for additional 10058-F4 tools to understand the effect of pharmacological inhibition of PI3K isoforms in lymphocytes. In this study, we tested the effects of a potent and selective p110 inhibitor, IPI-3063, in assays of B cell function. We found that IPI-3063 potently reduced mouse B cell proliferation, survival, and plasmablast differentiation while increasing antibody class switching to IgG1, almost to the same degree as a pan-PI3K inhibitor. Similarly, IPI-3063 potently inhibited human B cell proliferation encoding p110 cause a human immunodeficiency known as activated PI3K delta syndrome (APDS), which is 10058-F4 usually associated with chronically activated lymphocytes that undergo apoptosis or senescence (6, 7). Therefore, p110 has been extensively analyzed as a potential target for treating B cell malignancies, B cell-mediated autoimmune diseases, and potentially APDS. Impressive responses in clinical trials of idelalisib (previously known as GS-1101 or CAL-101) led to FDA approval of this drug for treatment of certain B cell malignancies (8). Other p110 inhibitors have shown activity in animal models of autoimmunity. For example, IC87114 reduced autoantibody production in a rat model of collagen-induced arthritis (9). Another recently developed p110 inhibitor, AMG319, reduced KLH-specific IgM and IgG production (10) while duvelisib (IPI-145), a dual p110/ inhibitor, showed potent activity in reducing inflammation in collagen-induced arthritis, ovalbumin-induced asthma, and systemic lupus erythematosus rodent models (11). Currently, however, you will find no approved treatments targeting p110 in B-cell-mediated autoimmune diseases. Additional p110 inhibitors with high potency and selectivity are needed as research tools for B cell biology and as potential lead compounds for B cell-driven diseases. Characterizing the effects of isoform-selective PI3K inhibitors on normal B cell function will provide insight toward obtaining effective therapeutic windows that can target B cell malignancies while maintaining effective host defense and may justify clinical exploration of these inhibitors in treating B cell-mediated autoimmune disease. Previous studies have exhibited that p110 is not the only PI3K isoform that contributes to B cell function. We used isoform-selective compounds to show that acute inhibition of either p110 or p110 partially reduce signaling and functional responses in activated B cells (12). Genetic analysis has shown partially overlapping functions of p110 and p110 in B cell development (13). Little is known about the role of the class IB isoform p110 in B cells. In T cells, p110 plays a role in early development and is important for trafficking of activated effector cells (14, 15). One study reported that mice lacking both p110 and p110 experienced greater defects in B cell survival and proliferation compared to p110 knockout alone (16). The effects of chemical p110 inhibition on B cell function have not been reported. In this 10058-F4 study, we utilized Rabbit Polyclonal to USP19 a novel, potent, and selective p110 inhibitor, IPI-3063 (Table ?(Table1)1) that has good pharmacokinetics in mice (11). Here, we tested the effects of IPI-3063 on mouse B cell survival, proliferation, and differentiation. We found that IPI-3063 is usually highly potent, modulating B cell responses at low nanomolar concentrations to an extent much like a pan-PI3K inhibitor. In contrast, a selective chemical inhibitor of p110 experienced no effect in various assays of B cell function. We also tested a novel dual p110/ inhibitor, IPI-443 (Table ?(Table1),1), to determine whether p110 inhibition increases the effects beyond blockade of p110 alone. Dual inhibition of p110/ with IPI-443 experienced comparable effects to IPI-3063 on B cell function. These results confirm that p110 is the dominant isoform that mediates B cell responses to diverse stimuli and establish that IPI-3063 is usually a highly potent molecule to probe p110 function in immune cells. Table 1 Summary of IC50 values for IPI-3063 and IPI-443 using purified enzymes. and did not test the role of p110 could indirectly impact B cell function. Small molecule inhibitors that are selective for single PI3K isoforms or pairs of isoforms have been highly useful in delineating the shared and distinct functions of PI3K enzymes.