Parsaclisib

Parsaclisib is an inhibitor of PI3Kδ (IC₅₀ = 1 nM).¹ It is selective for PI3Kδ over PI3Kα, PI3Kβ, and PI3Kγ (IC₅₀s = >10,000 nM for all), as well as a panel of 192 additional kinases and a panel of 70 ion channels and transporters at 1 µM. Parsaclisib inhibits the proliferation of primary human B cells (IC₅₀ = 0.2 nM) and the production of cytokines in memory T cells (IC₅₀s = 0.2-1.5 nM). It also inhibits the differentiation of naïve isolated human T cells into Th1, Th2, or Th17 T helper cells. It inhibits the proliferation of JeKo-1, Mino, Rec-1, and JVM-2 lymphoma cells (IC₅₀s = <10 nM for all) and Pfeiffer, SU-DHL-5, SU-DHL-6, and WSU-NHL diffuse large B cell lymphoma (DLBCL) cells (IC₅₀s = 2-8 nM). In vivo, parsaclisib (0.1-10 mg/kg) reduces intratumoral phosphorylation of Akt and tumor growth in a Pfeiffer mouse xenograft model. Parsaclisib (3 mg/kg) reduces proteinuria, lymphadenopathy, and the severity of skin lesions in an MRL/MpJ-Fas lpr mouse model of spontaneous systemic lupus erythematosus (SLE).² It also reduces salivary levels of TNF superfamily member 13B (TNFSF13B), also known as B cell activating factor (BAFF), and plasma levels of anti-SS-related antigen A (anti-SSA) and anti-SSB autoantibodies in a NOD.ShiLtJ mouse model of Sjögren’s syndrome.

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1. Shin, N., Stubbs, M., Koblish, H., et al. Parsaclisib is a next-generation phosphoinositide 3-kinase δ inhibitor with reduced hepatotoxicity and potent antitumor and immunomodulatory activities in models of B-cell malignancy. J. Pharmacol. Exp. Ther. 374(1), 211-222 (2020).

2. Scuron, M.D., Fay, B.L., Connell, A.J., et al. The PI3Kδ inhibitor parsaclisib ameliorates pathology and reduces autoantibody formation in preclinical models of systemic lupus erythematosus and Sjӧgren’s syndrome. Int. Immunopharmacol. 98:107904, (2021).