The skin is an important physiological barrier against external stimuli, such as ultraviolet radiation (UV), xenobiotics, and bacteria. Dermal inflammatory reactions are associated with various skin disorders, including chemical-induced irritation and atopic dermatitis. Modulation of skin inflammatory response is a therapeutic strategy for skin diseases. Here, we synthesized chrysin-derivatives and identified the most potent derivative of Compound 6 (CPD 6). We evaluated its anti-inflammatory effects in vitro cells of macrophages and keratinocytes, and in vivo dermatitis mouse models. In murine macrophages stimulated by lipopolysaccharide (LPS), CPD 6 significantly attenuated the release of inflammatory mediators such as nitric oxide (NO) (IC50 for NO inhibition: 3.613 μM) and other cytokines. In cultured human keratinocytes, CPD 6 significantly attenuated the release of inflammatory cytokines induced by the combination of IFN-γ and TNF-α, UV irradiation, or chemical irritant stimulation. CPD 6 inhibited NFκB and JAK2/STAT1 signaling pathways, and activated Nrf2/HO-1 signaling. In vivo relevancy of anti-inflammatory effects of CPD 6 was observed in acute and chronic skin inflammation models in mice. CPD 6 showed significant anti-inflammatory properties both in vitro cells and in vivo dermatitis animal models, mediated by the inhibition of the NFκB and JAK2-STAT1 pathways and activation of Nrf2/HO-1 signaling. We propose that the novel chrysin-derivative CPD 6 may be a potential therapeutic agent for skin inflammation.
High level of plasma TGF-β is significantly correlated with poor outcomes with approved immune-oncology therapeutics. Poor clinical results for ALK5 inhibitors and bifunctional fusion protein targeting TGF-β and PD-L1 are also being reported in several clinical trials. Therefore, a novel therapeutic with superior efficacy differentiated from previous TGF-β modulators will demonstrate significant clinical outcomes in combination with immuno-oncology therapeutics. In TME, TGF-β and VEGF synergistically induce eradication of immunogenic tumors. Therefore, a dual-inhibitor targeting both ALK5 and VEGFR2 has high potential to demonstrate effective clinical efficacy against TGF-β- and VEGF-enriched tumors as a single or combination treatment. TU2218 is a highly potent, orally available inhibitor against ALK5 and VEGFR2 with an IC50 of 1.2 nM and 4.9 nM respectively. In a human PBMC assay, 0.5-1 μM TU2218 treatment significantly enhanced IFN-γ production or IFN-γ-producing T lymphocytes number by TGF-β-driven immunosuppression, but vactosertib, galunisertib and TGF-β neutralizing antibody did not have significant effects. In a human regulatory T cells assay, CD4+CD25+ Tregs suppressed the proliferation of naïve CD4+CD25- T cells after TCR triggering. In contrast, 0.5 μM TU2218 treated Tregs completely reversed the TCR-mediated proliferation of CD4+CD25- T cells. In addition, the immunomodulatory activity of TU2218 was analyzed on the co-culture system of cancer cells with human PBMC. In this assay, MCF-7 and HT-1080 displayed strong inhibitory effects on IFN-γ secretion of human PBMC, but TU2218 completely restored IFN-γ production compared with the poor effect of either vactosertib or TGF-β neutralizing antibody. In an NK assay, TGF-β reduced the level of surface proteins of NKG2D and NKp30 on CD56dim and CD56bright human primary NK cells and NK92 cell lines. TU2218 treatment completely reversed not only the inhibitory effect of TGF-β on the expression of NKG2D but also TGF-β-driven impairment of NK cytolytic activity for K562 cell lines on the co-culture system. Results show TU2218 possesses potent anti-cancer immune activities through boosting T and NK immunity as well as blocking Treg activity, implicating the mechanism of overcoming immune tolerance and reversing immunosuppression in TME. These effects of TU2218 in human immune cells would be a basis for novel combination options to develop promising therapeutics for patients with advanced cancer. Citation Format: Nam-Hoon Kim, Seong-Ho Kang, Jihyun Lee, Seung-Hyun Kim, Chan-Hee Yu, Jae Won Choi, Soyoun Ahn, Jeongmin Seo, Hun-Taek Kim. Functional characterization of TU2218, ALK5 and VEGFR2 dual inhibitor, on in vitro tumor immunity-mimetic systems [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5538.
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