The Selective Phosphoinoside-3-Kinase p110? Inhibitor IPI-3063 Potently Suppresses B Cell Survival, Proliferation, and Differentiation.

ABSTRACT: The class I phosphoinoside-3-kinases (PI3Ks) are important enzymes that relay signals from cell surface receptors to downstream mediators driving cellular functions. Elevated PI3K signaling is found in B cell malignancies and lymphocytes of patients with autoimmune disease. The p110? catalytic isoform of PI3K is a rational target since it is critical for B lymphocyte development, survival, activation, and differentiation. In addition, activating mutations in PIK3CD encoding p110? cause a human immunodeficiency known as activated PI3K delta syndrome. Currently, idelalisib is the only selective p110? inhibitor that has been FDA approved to treat certain B cell 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 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 in vitro. The p110? isoform has partially overlapping roles with p110? in B cell development, but little is known about its role in B cell function. We found that the p110? inhibitor AS-252424 had no significant impact on B cell responses. A novel dual p110?/? inhibitor, IPI-443, had comparable effects to p110? inhibition alone. These findings show that p110? is the dominant isoform mediating B cell responses and establish that IPI-3063 is a highly potent molecule useful for studying p110? function in immune cells.

SUBMITTER: Chiu H 

PROVIDER: S-EPMC5491903 | biostudies-other | 2017

REPOSITORIES: biostudies-other