JOURNAL OF MEDICINAL CHEMISTRY
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2025
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IF 6.8
Wei Zhu,Pei Zhao,Tingting Liu,Feng Gao,Qi Li,Xin Cai,Man Zhang,Alex Aliper,Feng Ren,Alex Zhavoronkov,Xiao Ding
The dual inhibition of SIK2/3 has been considered as a potential treatment approach for MEF2C-high acute myeloid leukemia (AML). Although diverse scaffolds of pan-SIK or SIK2/3 inhibitors have been reported, few of them showed sufficient in vitro or in vivo antitumor activity. Based on the proposed binding mode of the hit molecule (7), chemical space in the solvent/P-loop region was explored via fragment growing/replacement, supported by the generative chemistry platform. Further SAR exploration and ADME optimization led to the discovery of 7s, which exhibited excellent potency and strong selectivity in MEF2C high-expression cell lines over MEF2C-low cell lines. Moreover, oral administration of 7s was found to demonstrate significant tumor growth inhibition in a MV4-11 AML mice CDX model without any body weight loss. This work highlights the potential of targeting MEF2C-dependent AML by selective oral SIK2/3 inhibitors, which was supported by the generative models.
研究领域:
药理学
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肿瘤学
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药物化学
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血液学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2022
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IF 3.322
Tiantian Wang,Ruihe Zheng,Song Sun
Acute lung injury (ALI) is a significant cause of morbidity and mortality worldwide. To search for a new treatment for acute lung injury, we investigated the effect of escitalopram on lipopolysaccharide (LPS)-induced ALI. Our results showed that escitalopram inhibited salt-inducible kinase 2 (SIK2) activity (IC 50 = 6.36 ± 0.93 μM) and triggered histone deacetylase 4 (HDAC4) dephosphorylation . Following its dephosphorylation, HDAC4 translocated into the nucleus, promoted deacetylation and cytoplasmic shuttling of p65, thus inhibited LPS-induced pro-inflammatory cytokine production. Moreover, escitalopram markedly ameliorated the inflammatory responses, reduced neutrophils infiltration and attenuated LPS-induced pulmonary injury in mice. Taken together, we identified a previously unexplored role for escitalopram in SIK2/HDAC4/NF-κB pathway, therefore escitalopram may be considered as a new treatment for ALI.
研究领域:
药理学
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免疫学
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肺病学
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药物再利用
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产品关联
DOI
PubMed
高影响因子
BMC Pulmonary Medicine
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2022
·Vol. 22
·期 1
·1-11
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IF 3.32
Zou Liangneng,Hong Dequn,Li Kecong,Jiang Bingyuan
Background Pulmonary fibrosis is a fatal lung disease with complex pathogenesis and limited effective therapies. Salt-inducible kinase 2 (SIK2) is a kinase that phosphorylates CRTCs and regulates many physiological processes. However, the role of SIK2 on pulmonary fibrosis remains unclear, and whether SIK2 inhibitor can attenuate pulmonary fibrosis is unknown.MethodWe subjected human fetal lung fibroblasts (HFLs) to transforming growth factor-β1 (5 ng/mL) for 12 h, and examined the expression of SIK2, CRTCs and pCRTCs in fibroblasts by western-blot. To address the roles of SIK2 and CRTCs involved in the progression of pulmonary fibrosis, HFLs were treated with a small-molecule inhibitor ARN-3236 or by siRNA-mediated knockdown of SIK2 expression. Pulmonary fibrosis model was established with mice by exposing to bleomycin, and assessed by H&E and Masson’s trichrome staining. COL1A and α-SMA distributions were detected in lung tissues by immunohistochemical staining.Results We discovered that SIK2 and phosphorylated-CRTC2 were expressed at a low basal level in normal lung tissues and quiescent fibroblasts, but increased in fibrotic lung tissues and activated fibroblasts. Inhibition of SIK2 by ARN-3236 prevented the fibroblasts differentiation and extracellular matrix expression in HFLs and attenuated bleomycin-induced pulmonary fibrosis in mice. Mechanistically, inactivation of SIK2 resulted in the dephosphorylation and nuclear translocation of CRTC2. Within the nucleus, CRTC2 binds to CREB, promoting CREB-dependent anti-fibrotic actions.Conclusion In conclusion, our results elucidated a previously unexplored role of SIK2 in pulmonary fibrosis, and identified SIK2 as a new target for anti-fibrosis medicines.
研究领域:
肺科学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
IMMUNOLOGY AND CELL BIOLOGY
·
2026
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IF 3.3
Yadi Li,Xiaoqian Zhou,Zhusheng Yang,Xiumin Yang,Aihua Wei
Psoriasis, a chronic inflammatory skin disease, involves dysregulated immune responses and keratinocyte hyperproliferation. The role of salt-inducible kinase 2 (SIK2) in modulating interleukin-23 (IL-23) secretion via C–X–C motif chemokine ligand 5 (CXCL5) in neutrophils has not been fully explored. We combined in vivo and in vitro approaches to examine SIK2's role in an imiquimod (IMQ)-induced psoriasis model and activated neutrophils. Mice underwent intradermal injections of lentiviruses overexpressing SIK2, CXCL5, or both, while in vitro experiments involved transfecting activated neutrophils with these constructs. Assessments included ear thickness, cellular and neutrophil infiltration through histological and immunofluorescence techniques, and analysis of gene and protein expressions via quantitative real-time PCR (qRT-PCR), immunohistochemistry (IHC), and Western blot. Additionally, cell viability, proliferation, and cytokine levels in N -formylmethionyl-leucyl-phenylalanine (fMLF) treated neutrophils were evaluated using cell-counting kit-8 (CCK8), 5-ethynyl-2′-deoxyuridine (EdU) incorporation, and Enzyme-Linked Immunosorbent Assay (ELISA). Overexpression of SIK2 significantly reduced ear thickness, cellular and neutrophil infiltration, IL-1β, tumor necrosis factor-alpha (TNF-α), CXCL5, IL-23 and phosphorylated Yes-associated protein (p-YAP) levels, and increased SIK2 levels in IMQ mice model, but overexpression of CXCL5 reversed these effects. In vitro , SIK2 overexpression resulted in reduced cell viability and proliferation, with corresponding reductions in IL-1β, IL-17, IL-23, and Matrix Metallopeptidase 9 levels, whereas overexpression of CXCL5 reversed these effects. Our findings suggest that SIK2 acts as a critical modulator in psoriasis by influencing CXCL5-mediated IL-23 secretion in neutrophils, underscoring the potential of SIK2 as a therapeutic target to alleviate the inflammatory responses in psoriasis.
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DOI
高影响因子
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