Acetyl‐11‐keto‐β‐boswellic acid (AKBA) is known to inhibit the growth of glioblastoma (GBM) cells and subcutaneous GBM. A series of acetyl‐11‐keto‐β‐boswellic acid (AKBA) derivatives containing the oxime‐ester functionality or amide side chains were synthesized, and their anti‐GBM activities were evaluated. Some of these compounds exhibited significant inhibitory activity against cell proliferation in U87 and U251 GBM cell lines, with IC50 values in the micromolar concentration range. Cellular thermal shift analysis showed that A‐01 and A‐10 improved the thermal stability of FOXM1, indicating that these highly active compounds may directly bind to FOXM1 in cells. Docking studies of the two most active compounds, A‐01 and A‐10, revealed key interactions between these compounds and the active site of FOXM1, in which the amide moiety at the C‐24 position was essential for improving the activity. These results suggested that A‐10 is a suitable lead molecule for the development of FOXM1 inhibitors. Thus, the rational design of AKBA derivatives with amide side chains holds significant potential for discovering of a new class of triterpenoids capable of inhibiting GBM cell proliferation.

2024-04-01·International immunopharmacology

FOXA1-Driven pathways exacerbate Radiotherapy-Induced kidney injury in colorectal cancer

Article

作者: Yuan, Huiqiong ; Zhang, Yuling ; Yang, Jingyuan ; Yu, Tao ; Wu, Yanni ; Li, Li ; Zhang, Minhai ; Wang, Jingfeng ; Liang, Guodong

OBJECTIVE:

This study aimed to investigate the role of FOXA1 in acute kidney injury (AKI) induced by radiotherapy in colorectal cancer. Although FOXA1 is known to be aberrantly expressed in malignant tumors, its contribution to AKI remains unclear. This study aimed to explore the involvement of FOXA1 in AKI induced by radiotherapy in colorectal cancer and its influence on the regulation of downstream target genes.

METHODS:

Firstly, a transcriptome analysis was performed on mice to establish a radiation-induced AKI model, and qPCR was used to determine the expression of FOXA1 in renal cell injury models induced by X-ray irradiation. Additionally, FOXA1 was silenced using lentiviral vectors to investigate its effects on the apoptosis of mice with radiation-induced AKI and HK-2 cells. Next, bioinformatics analysis and various experimental validation methods such as ChIP assays, co-immunoprecipitation, and dual-luciferase reporter assays were employed to explore the relationship between FOXA1 and the downstream regulatory factors ITCH promoter and the ubiquitin ligase-degradable TXNIP. Finally, lentiviral overexpression or knockout techniques were used to investigate the impact of the FOXA1/ITCH/TXNIP axis on oxidative stress and the activation of inflammatory body NLRP3.

RESULTS:

This study revealed that FOXA1 was significantly upregulated in the renal tissues of mice with radiation-induced AKI and in the injured HK-2 cells. Furthermore, in vitro cell experiments and animal experiments demonstrated that FOXA1 suppressed the transcription of the E3 ubiquitin ligase ITCH, thereby promoting apoptosis of renal tubular cells and causing renal tissue damage. Further in vivo animal experiments confirmed that TXNIP, a protein degraded by ITCH ubiquitination, could inhibit oxidative stress and the activation of NLRP3 inflammasome in the AKI mouse model.

CONCLUSION:

FOXA1 enhances oxidative stress, cell apoptosis, and NLRP3 inflammasome activation by regulating the ITCH/TXNIP axis, thereby exacerbating radiotherapy-induced AKI.

2023-12-31·Journal of enzyme inhibition and medicinal chemistry

Aromatic sulphonamides of aziridine-2-carboxylic acid derivatives as novel PDIA1 and PDIA3 inhibitors

Article

作者: Fedak, F. A. ; Kanepe-Lapsa, I. ; Zelencova-Gopejenko, D. ; Kalvins, I. ; Domracheva, I. ; Kramkowski, K. ; Chlopicki, S. ; Milczarek, M. ; Przyborowski, K. ; Walczak, M. ; Andrianov, V. ; Wietrzyk, J. ; Stojak, M.

In this study, we report a series of newly synthesised sulphonamides of aziridine-2-carboxylic acid (Az-COOH) ester and amide analogues as potent protein disulphide isomerase (PDI, EC 5.3.4.1) inhibitors. The inhibitory activity on PDI was determined against recombinant human PDIA1 and PDIA3 proteins using an insulin reduction assay. These compounds in low micromolar to low nanomolar concentrations showed the effective in vitro inhibitory properties of PDIA1 with weaker effects on PDIA3. Complexes of ¹⁵N- and ¹⁵N,¹³C- uniformly labelled recombinant human PDIA1a with two PDIA1 inhibitors were produced and investigated by a protein nuclear magnetic resonance (NMR) spectroscopy. It was found that both C53 and C56 of the PDIA1 enzyme were involved in covalent binding. Finally, in a range of pharmacological studies, we demonstrated that investigated compounds displayed anti-cancer and anti-thrombotic activity. These findings demonstrate that sulphonamides of Az-COOH derivatives are promising candidates for the development of novel anti-cancer and anti-thrombotic agents.

100 项与 FOXA1 inhibitors (Curve Therapeutics) 相关的药物交易

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