Acute lung injury (ALI), a leading pulmonary inflammatory disorder, is associated with high morbidity and mortality rates. AXL, a member of the TAM family, plays a significant role in the innate immune and inflammatory responses. This study aimed to evaluate the therapeutic potential of C1632 and its mechanisms in the treatment of LPS-induced ALI/ARDS. The results demonstrated that C1632 pretreatment inhibited the transcription, expression, and secretion of LPS-induced inflammatory factors (IL-6, TNF-α) and vascular adhesion molecules (VCAM-1, ICAM-1). Furthermore, it reduced inflammatory cell infiltration in the lungs, thereby alleviating LPS-induced histopathological changes and lung injury in mice. Mechanistically, C1632 suppressed AXL transcription and expression, which inhibited the activation of the MAPK/NF-κB signaling pathway triggered by LPS stimulation. Both in vitro and in vivo studies confirmed that C1632 administration did not exhibit significant cytotoxicity. Additionally, it did not cause functional or structural damage to the liver and kidneys in mice, nor did it induce other acute toxic effects. In summary, these findings suggest that AXL is a novel target for MAPK/NF-κB signaling pathway mediated anti-inflammatory treatment and C1632 is a promising therapeutic agent for ALI/ARDS treatment.

01 Oct 2023·European Journal of Pharmacology

C1632 inhibits ovarian cancer cell growth and migration by inhibiting LIN28 B/let-7/FAK signaling pathway and FAK phosphorylation

Article

Author: Han, Haoyi ; Zhang, Qian ; Lin, Feng ; Zheng, Ruiling ; Shi, Mengyun ; Zhang, Xin

The highly conserved RNA-binding protein LIN28B and focal adhesion kinase (FAK) are significantly upregulated in ovarian cancer (OC), serving as markers for disease progression and prognosis. Nonetheless, the correlation between LIN28B and FAK, as well as the pharmacological effects of the LIN28 inhibitor C1632, in OC cells have not been elucidated. The present study demonstrates that C1632 significantly reduced the rate of DNA replication, arrested the cell cycle at the G0/G1 phase, consequently reducing cell viability, and impeding clone formation. Moreover, treatment with C1632 decreased cell-matrix adhesion, as well as inhibited cell migration and invasion. Further mechanistic studies revealed that C1632 inhibited the OC cell proliferation and migration by concurrently inhibiting LIN28 B/let-7/FAK signaling pathway and FAK phosphorylation. Furthermore, C1632 exhibited an obvious inhibitory effect on OC cell xenograft tumors in mice. Altogether, these findings identified that LIN28 B/let-7/FAK is a valuable target in OC and C1632 is a promising onco-therapeutic agent for OC treatment.

01 Mar 2023·Molecular Therapy

Targeting Lin28 axis enhances glypican-3-CAR T cell efficacy against hepatic tumor initiating cell population

Article

Author: Cunningham, David M ; Patra, Tapas ; Toth, Karoly ; Meyer, Keith ; Ray, Ranjit ; Heczey, Andras ; Ray, Ratna B

Overexpression of Lin28 is detected in various cancers with involvement in the self-renewal process and cancer stem cell generation. In the present study, we evaluated how the Lin28 axis plays an immune-protective role for tumor-initiating cancer cells in hepatocellular carcinoma (HCC). Our result using HCC patient samples showed a positive correlation between indoleamine 2,3-dioxygenase-1 (IDO1), a kynurenine-producing enzyme with effects on tumor immune escape, and Lin28B. Using in silico prediction, we identified a Sox2/Oct4 transcriptional motif acting as an enhancer for IDO1. Knockdown of Lin28B reduced Sox2/Oct4 and downregulated IDO1 in tumor-initiating hepatic cancer cells. We further observed that inhibition of Lin28 by a small-molecule inhibitor (C1632) suppressed IDO1 expression. Suppression of IDO1 resulted in a decline in kynurenine production from tumor-initiating cells. Inhibition of the Lin28 axis also impaired PD-L1 expression in HCC cells. Consequently, modulating Lin28B enhanced in vitro cytotoxicity of glypican-3 (GPC3)-chimeric antigen receptor (CAR) T and NK cells. Next, we observed that GPC3-CAR T cell treatment together with C1632 in a HCC xenograft mouse model led to enhanced anti-tumor activity. In conclusion, our results suggest that inhibition of Lin28B reduces IDO1 and PD-L1 expression and enhances immunotherapeutic potential of GPC3-CART cells against HCC.

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Indication	Highest Phase	Country/Location	Organization	Date
COVID-19	Preclinical	-	Tsinghua University	27 Dec 2022

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