Telatinib

Endometrial carcinoma (EC) is a type of cancer that originates in the lining of the uterus, known as the endometrium. It is associated with various treatment options such as surgery, radiation therapy, chemotherapy, and hormone therapy, each presenting unique challenges and limitations. Beta-catenin, a protein involved in the development and progression of several cancers, including EC, plays a crucial role. Abnormal beta-catenin signaling is often linked to the emergence of specific EC subtypes, affecting tumor growth and invasion.

The study's objective is to identify compounds targeting the beta-catenin protein for treating endometrial cancer (EC) using in silico drug design. Our approach includes molecular docking to evaluate binding affinities, ADME profiling for pharmacokinetic properties, toxicity assessments, and molecular dynamics simulations to assess compound stability and interactions.

Approximately one thousand anti-cancer phytochemicals were sourced from PubChem and subjected to molecular docking simulations against the beta-catenin protein. The compounds were evaluated based on their binding affinities, with the top five selected for further analysis. These five molecules underwent toxicity and ADME profiling. The Prediction of Activity Spectra for Substances (PASS) tool was used to identify compounds targeting CTNNB1. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were employed to establish quantitative structure-activity relationship (QSAR) models for the five CTNNB1 antagonist molecules.

The selected five compounds, namely Pazopanib, Binimetinib, Telatinib, 4-(2,3-Dihydrobenzo[ b][1,4]dioxin-6-yl)-3-((5-nitrothiazol-2-yl)thio)-1H-1,2,4-triazol-5(4H)-one, and Ribavirin, demonstrated efficacy against CTNN1. MD simulations of the docked complexes confirmed the stability of these drugs in binding to the target protein. All five molecules showed promising safety and effectiveness profiles according to their ADME and toxicity evaluations.

Through a comprehensive screening process employing in silico drug design methods, this study successfully identified five potential human anticancer drug candidates targeting the beta-catenin protein. These findings offer a foundation for further experimental validation and development towards the treatment of EC.

Chondroitin polymerizing factor (CHPF) has been found to be involved in the development of numerous cancers and correlated with poor prognosis. However, its role in the tumorigenesis and development of colorectal cancer (CRC) remains unknown.

In our research, we explored CHPF expression and clinicopathological characteristics using The Cancer Genome Atlas Program (TCGA), UALCAN, GSE9348, TIMER2.0 and The Human Protein Atlas (HPA) database, in addition, we validated CHPF expression in CRC cell lines by Real-Time Quantitative PCR (qRT-PCR) and Western blot (WB). KM-Plotter, PrognoScan and TCGA were also utilized to verify its prognosis value in CRC. Small-interfer RNA (Si-RNA) was used to perform Cell Counting Kit-8 (CCK8), colony formation, 5-ethynyl-2'-deoxyuridine (EDU), transwell and wound healing assays to testify its function on the tumor progression. Based on TCGA database, we probed potential biological mechanism by which CHPF play its role via clusterProfiler package and GEPIA database and we validated their correlation by WB assay. Moreover, we explored its potential association with the tumor microenvironment (TME), immune infiltrated cells, immune checkpoints, tumor mutation burden (TMB) as well as microsatellite instability (MSI), and investigated immunotherapy sensitivity via Tumor Immune Dysfunction and Exclusion (TIDE) algorithm as well as potentially effective therapeutic drugs via pRRophetic algorithm.

CHPF was identified upregulated in CRC tissues and cells, correlated with poor prognosis, and nodal metastasis status, stage and histological subtype. Down-regulation of CHPF inhibited CRC cell proliferation, migration and its expression correlated with wnt pathway key molecules. In addition, high expression of CHPF was positively correlated with TME scores, Regulatory T cells (Tregs) cell infiltration degree, Programmed death-1 (PD-1), MSI-high (MSI-H), and TIDE scores, however, not with TMB. Targeted drug analysis showed that patients with high CHPF expression were more sensitive to telatinib, recaparib, serdemetan, and trametinib.

CHPF could promote the proliferation and migration of CRC cells and lead to poor prognosis, possibly through wnt pathways as well as changes in TME. Patients with high expression of CHPF had poor efficacy in immunotherapy, which might be related to Tregs cell infiltration. Above all, it might offer more reliable guidance for future immunotherapy.