Discovery of N-{5-[3-(3-hydroxypiperidin-1-yl)-1,2,4-oxadiazol-5-yl]-4-methyl-1,3-thiazol-2-yl}acetamide (TASP0415914) as an orally potent phosphoinositide 3-kinase γ inhibitor for the treatment of inflammatory diseases

Oka, Yusuke; Yabuuchi, Tetsuya; Oi, Takahiro; Kuroda, Shoichi; Fujii, Yasuyuki; Ohtake, Hidenori; Wakahara, Shunichi; Kimura, Kayo; Fujita, Komei; Endo, Mayumi; Taguchi, Kyoko; Sekiguchi, Yoshinori

doi:10.1016/j.bmc.2013.10.042

Cited by 21 publications

(16 citation statements)

References 21 publications

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“…Given the important roles uncovered for PI3K in promoting inflammation, many studies have investigated the effects of pharmacological inhibition of PI3K isoforms in animal models of inflammatory joint disease. The PI3Kγ inhibitors AS605240 and TASP0415914 reduced the symptoms of collagen-induced arthritis (CIA) [27, 28]. ZSTK474, a pan-class I PI3K inhibitor, was also found to improve inflammation and disease progression in RA animal models [29].…”

Section: Discussionmentioning

confidence: 99%

PI3K/Akt inhibitor partly decreases TNF-α-induced activation of fibroblast-like synoviocytes in osteoarthritis

et al. 2019

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BackgroundThe Cadherin-11 and PI3K/Akt pathway are increasingly recognized as the potential therapeutic target of osteoarthritis (OA) synovitis. The study aimed to investigate the role of PI3K/Akt signaling pathway in the expression of Cadherin-11 and migration and invasive capacity of fibroblast-like synoviocytes (FLS) of OA patients under stimulation of TNF-α and to explore the effect of the PI3K/Akt inhibitor and Cadherin-11 antibody in the therapy of the collagenase-induced osteoarthritis (CIOA) mice.MethodsFLS were primarily cultured from synovium of osteoarthritic patients during total knee arthroplasty. Under the simulation of TNF-α, with or without PI3K/Akt inhibitor LY294002, Cadherin-11 expression was detected by real-time PCR and Western blot, as well as the migration and invasive capacity changes of OA FLS. Cadherin-11 antibody was injected intraarticularly or LY294002 was injected intraperitoneally in CIOA mice to evaluate the changes of synovitis score, cartilage damage, and Cadherin-11 expression.ResultsTNF-α stimulation increased Cadherin-11 expression at mRNA and protein level in OA FLS and also increased the phosphorylation-dependent activation of Akt. PI3K inhibitor LY294002 attenuated TNF-α-induced overexpression of Cadherin-11 and decreased the invasive capacity of OA FLS. Intraperitoneal injection of PI3K inhibitor LY294002 could decrease the Cadherin-11 protein expression in synovium of CIOA mice, although it has no significant inhibitory effect on synovitis and cartilage damage. Intraarticular injection of Cadherin-11 antibody attenuated the synovitis and cartilage damage in the CIOA joints and decreased Cadherin-11 expression in the synovial lining.ConclusionsPI3K/Akt pathway was associated with TNF-α-induced activation of OA FLS, which may involve in the pathogenesis of osteoarthritis. Anti-Cadherin-11 therapy in CIOA mice could attenuate the pathological changes of OA joints.

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Section: Discussionmentioning

confidence: 99%

PI3K/Akt inhibitor partly decreases TNF-α-induced activation of fibroblast-like synoviocytes in osteoarthritis

et al. 2019

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“…Inhibitors of PI3Kδ, PI3Kγ and dual selective inhibition are also effective in alleviating the symptoms of RA in animal models. The PI3Kγ inhibitors AS605240, TASP0415914 and CZC24823 reduced the development of collagen induced arthritis (CIA) [39,51,52], and genetic as well as pharmacological inhibition improved symptoms in the effector phase K/BxN serum transfer and αCII models, mainly driven by neutrophilic inflammation [52,53]. Neutrophil migration to LTB 4 is markedly reduced by dual PI3Kγ/δ inhibition compared to inhibition of either isoform alone [53].…”

Section: Targeting Class I Pi3k In Autoimmune and Inflammatory Disordersmentioning

confidence: 99%

PI3K inhibitors in inflammation, autoimmunity and cancer

Stark

Sriskantharajah

Hessel

et al. 2015

Current Opinion in Pharmacology

258

178

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The healthy immune system protects against infection and malignant transformation without causing significant damage to host tissues. Immune dysregulation results in diverse pathologies including autoimmune disease, chronic inflammatory disorders, allergies as well as immune deficiencies and cancer. Phosphoinositide 3-kinase (PI3K) signalling has been shown to be a key pathway in the regulation of the immune response and continues to be the focus of intense research. In recent years we have gained detailed understanding of PI3K signalling, and saw the development of potent and highly selective small molecule inhibitors, of which several are currently in clinical trials for the treatment of immune-related disorders and cancer. The role of PI3K signalling in the immune response has been the subject of detailed reviews; here we focus on relevant recent progress in pre-clinical and clinical development of PI3K inhibitors.

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“…To test the hypothesis that pharmacological inhibition of PI3K-γ in tumor-associated myeloid cells could block their immune-suppressive function and lead to enhanced immune attack on tumor cells, a potent and selective synthetic small-molecule inhibitor of the PI3K-γ isoform was needed. Although inhibitors of PI3K-γ have been reported over the past decade, their selectivity for PI3K-γ over other PI3K isoforms or pharmacologic properties were until recently not suitable for assessment of inhibiting only PI3K-γ in vivo. − Hence, we set out to identify potent and selective inhibitors of PI3K-γ with desirable drug-like properties.…”

mentioning

confidence: 99%

Discovery of a Selective Phosphoinositide-3-Kinase (PI3K)-γ Inhibitor (IPI-549) as an Immuno-Oncology Clinical Candidate

Evans

Liu

Lescarbeau

et al. 2016

ACS Med. Chem. Lett.

125

113

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Discovery of N-{5-[3-(3-hydroxypiperidin-1-yl)-1,2,4-oxadiazol-5-yl]-4-methyl-1,3-thiazol-2-yl}acetamide (TASP0415914) as an orally potent phosphoinositide 3-kinase γ inhibitor for the treatment of inflammatory diseases

Cited by 21 publications

References 21 publications

PI3K/Akt inhibitor partly decreases TNF-α-induced activation of fibroblast-like synoviocytes in osteoarthritis

PI3K/Akt inhibitor partly decreases TNF-α-induced activation of fibroblast-like synoviocytes in osteoarthritis

PI3K inhibitors in inflammation, autoimmunity and cancer

Discovery of a Selective Phosphoinositide-3-Kinase (PI3K)-γ Inhibitor (IPI-549) as an Immuno-Oncology Clinical Candidate

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