PO‐322 exerts potent immunosuppressive effects in vitro and in vivo by selectively inhibiting SGK1 activity

Abstract

Background and Purpose Immunosuppressive drugs have shown great promise in treating autoimmune diseases in recent years. A series of novel oxazole derivatives were screened for their immunosuppressive activity. PO‐322 [1H‐indole‐2,3‐dione 3‐(1,3‐benzoxazol‐2‐ylhydrazone)] was identified as the most effective of these compounds. Here, we have investigated the mechanism(s) underlying the inhibition of T‐cell proliferation in vitro by PO‐322, as well as its effects on the delayed‐type hypersensitivity (DTH) response and imiquimod‐induced dermatitis in vivo. Experimental Approach T‐cell proliferation and apoptosis were analysed with flow cytometry. Cell viability was assessed with a CCK‐8 assay. Protein kinase activity was assessed by SelectScreen Kinase Profiling Services. The phosphorylation of signal‐regulated molecules was measured by Western blot. Cytokine levels were determined by elisa. The effect of PO‐322 on DTH and imiquimod‐induced dermatitis was evaluated in BALB/c mice. Key Results PO‐322 inhibited human T‐cell proliferation with anti‐CD3/anti‐CD28 mAbs or alloantigen without significant cytotoxicity. Importantly, PO‐322 was a selective inhibitor of the serum‐ and glucocorticoid‐regulated kinase 1 (SGK1) and decreased NDRG1 phosphorylation but not p70S6K, STAT5, Akt, or ERK1/2 phosphorylation. Furthermore, PO‐322 inhibited IFN‐γ, IL‐6, and IL‐17 expression but not IL‐10 expression. Finally, treatment with PO‐322 was safe and effective for ameliorating the DTH response and imiquimod‐induced dermatitis in mice. Conclusions and Implications PO‐322 exerted immunosuppressive activity in vitro and in vivo by selectively inhibiting SGK1 activity. PO‐322 represents a potential lead compound for the design and development of new drugs for the treatment of autoimmune diseases.

SGK1 in Human Cancer: Emerging Roles and Mechanisms

“…In recent years, as one of the laboratories studying the role and function of SGK1 in human cancer, we identified SGK1 as a crucial key molecule involved in prostate cancer (PCa) progression through regulation of cell apoptosis, cell cycle, invasion/migration, and autophagy ( 19 , 20 ). The role of SGK1 in human cancer has been explored in numerous clinical, translational, and basic studies ( 6 , 11 , 12 ). An increasing amount of scientific evidence has confirmed the therapeutic potential of SGK1 in human cancer ( 11 ), and a critical review is necessary.…”

“…The role of SGK1 in human cancer has been explored in numerous clinical, translational, and basic studies ( 6 , 11 , 12 ). An increasing amount of scientific evidence has confirmed the therapeutic potential of SGK1 in human cancer ( 11 ), and a critical review is necessary. In this review, we focus on the diagnostic and prognostic value of SGK1 in human cancer, which has not yet been critically reviewed elsewhere.…”

“…Ion channels (e.g., ENaC and KCNE1/KCNQ1), carriers (such as NCC and NHE3), Na(+)/K(+)-ATPase, enzymes (including GSK3), and transcription factors or regulators (including forkhead box O 3a (FOXO3a), NF-kappaB, b-catenin and p27) are extensively regulated by SGK1 (6). Thus, SGK1 impacts a wide variety of physiological functions (7) and plays an active role in the pathophysiology of several disorders, including hypertension (8), diabetes (9), inflammation (10), autoimmune disease (11), and tumor growth (12). SGK1 belongs to the "AGC" subfamily of protein kinases, containing 60 members, including PKA, PKG, and PKC, which all share a conserved catalytic kinase domain (13).…”

Serum and glucocorticoid-regulated kinase 1: Structure, biological functions, and its inhibitors

“…3.2.1 PO-322 (5) Lai et al (2020) identified PO-322 (5) as a selective SGK1 inhibitor that acts as an immunosuppressant. Initially, the authors examined the effects of in-house oxazole derivatives on T cell proliferation following anti-CD3 or anti-CD28 stimulation.…”