Fused in silico and bioactivity evaluation method for drug discovery: T001-10027877 was identified as an antiproliferative agent that targets EGFR and EGFR.

Background: Facing the significant challenge of overcoming drug resistance in cancer treatment, particularly resistance caused by mutations in epidermal growth factor receptor (EGFR), the aim of our study was to identify potent EGFR inhibitors effective against the mutant, a key player in resistance mechanisms.

Methods: Our integrated in silico approach harnessed machine learning, virtual screening, and activity evaluation techniques to screen 5105 compounds from three libraries, aiming to find candidates capable of overcoming the resistance conferred by the T790M and C797S mutations within EGFR. This methodical process narrowed the search down to six promising compounds for further examination.

Visualization of nonsmall-cell lung cancer by near-infrared fluorescence imaging with tumor-targeting peptide ABT-510.

Nonsmall-cell lung cancer (NSCLC) is the most frequent type of lung cancer, with early surgical treatment proving vital for prolonged patient survival. However, precise visualization of NSCLC remains a challenge due to limited molecular imaging probes, the unique anatomical structure of the lungs, and respiratory movement interference. In this study, we investigated the potential utility of CD36, which is highly expressed in NSCLC, as an imaging target.

In silico method and bioactivity evaluation to discover novel antimicrobial agents targeting FtsZ protein: Machine learning, virtual screening and antibacterial mechanism study.

This research paper utilizes a fused-in-silico approach alongside bioactivity evaluation to identify active FtsZ inhibitors for drug discovery. Initially, ROC-guided machine learning was employed to obtain almost 13182 compounds from three libraries. After conducting virtual screening to assess the affinity of 2621 acquired compounds, cluster analysis and bonding model analysis led to the discovery of five hit compounds.

Virtual Screening, Molecular Dynamics Simulation, and Bioactivity Assessment Validate T13074 as a Dual-Target EGFR/c-Met Inhibitor.

Objectives: The objective of this study is to identify dual-target inhibitors against EGFR/c-Met through virtual screening, dynamic simulation, and biological activity evaluation. This endeavor is aimed at overcoming the challenge of drug resistance induced by L858R/T790M mutants.

Methods: Active structures were gathered to construct sets of drug molecules.

Novel Near-Infrared Fluorescent Probe for Hepatocyte Growth Factor Imaging in Surgical Navigation of Colorectal Cancer.

Despite recent advancements in colorectal cancer (CRC) treatment, the prognosis remains unfavorable primarily due to high recurrence and liver metastasis rates. Fluorescence molecular imaging technologies, combined with specific probes, have gained prominence in facilitating real-time tumor resection guided by fluorescence. Hepatocyte growth factor (HGF) is overexpressed in CRC, but the advancement of HGF fluorescent probes has been impeded by the absence of effective HGF-targeting small-molecular ligands.

Design, synthesis, and evaluation of antitumor activity of Mobocertinib derivatives, a third-generation EGFR inhibitor.

Mobocertinib, as a structural analog of the third generation TKI Osimertinib, can selectively act on the EGFRex20 mutation. We have structurally modified Mobocertinib to obtain new EGFR inhibitors. In this paper, we chose Mobocertinib as a lead compound for structural modification to investigate the effect of Mobocertinib derivatives on EGFR mutation.

Preclinical evaluation of AGTR1-Targeting molecular probe for colorectal cancer imaging in orthotopic and liver metastasis mouse models.

Despite advancements in colorectal cancer (CRC) treatment, the prognosis remains unfavorable for patients with distant liver metastasis. Fluorescence molecular imaging with specific probes is increasingly used to guide CRC surgical resection in real-time and treatment planning. Here, we demonstrate the targeted imaging capacity of an MPA-PEG-N-Ang II probe labeled with near-infrared (NIR) fluorescent dye targeting the angiotensin II (Ang II) type 1 receptor (AGTR1) that is significantly upregulated in CRC.

Rational design and synthesis of 2,4-dichloro-6-methyl pyrimidine derivatives as potential selective EGFR inhibitors for the treatment of non-small cell lung cancer.

Many patients with non-small cell lung cancer (NSCLC) initially benefit from epidermal growth factor receptor (EGFR) targeted therapy. Unfortunately, varying degrees of resistance or side effects eventually develop. Overcoming and preventing the resistance and side effects of EGFR inhibitors has become a hot topic of research today.

T6496 targeting EGFR mediated by T790M or C797S mutant: machine learning, virtual screening and bioactivity evaluation study.

Acquired resistance to EGFR is a major impediment in lung cancer treatment, highlighting the urgent need to discover novel compounds to overcome EGFR drug resistance. In this study, we utilized in silico methods and bioactivity evaluation for drug discovery to identify novel active anticancer agents targeting EGFR and EGFR. Firstly, we employed ROC-guided machine learning to retrieve nearly 7,765 compounds from a collection of three libraries (comprising over 220,000 compounds).

screening combined with bioactivity evaluation to identify AMI-1 as a novel anticancer compound by targeting AXL.

Recently, some studies have proven that AXL plays a crucial role in the drug resistance of tumors. At present, no AXL inhibitors on the market and it is essential to discover novel compounds targeting AXL to overcome resistance. In this work, based on the anchor structure, 21,313 compounds were obtained by substructure search from more than 400,000 compounds.

Novel GRPR-Targeting Peptide for Pancreatic Cancer Molecular Imaging in Orthotopic and Liver Metastasis Mouse Models.

Despite advancements in pancreatic cancer treatment, it remains one of the most lethal malignancies with extremely poor diagnosis and prognosis. Herein, we demonstrated the efficiency of a novel peptide GB-6 labeled with a near-infrared (NIR) fluorescent dye 3H-indolium, 2-[2-[2-[(2-carboxyethyl)thio]-3-[2-[1,3-dihydro-3,3-dimethyl-5-sulfo-1-(3-sulfopropyl)-2H-indol-2-ylidene]ethylidene]-1-cyclohexen-1-yl]ethenyl]-3,3-dimethyl-5-sulfo-1-(3-sulfopropyl)-, inner salt (MPA) and radionuclide technetium-99m (Tc) as targeting probes using the gastrin-releasing peptide receptor (GRPR) that is overexpressed in pancreatic cancer as the target. A short linear peptide with excellent in vivo stability was identified, and its radiotracer [Tc]Tc-HYNIC-PEG-GB-6 and the NIR probe MPA-PEG-GB-6 exhibited selective and specific uptake by tumors in an SW1990 pancreatic cancer xenograft mouse model.

Preclinical Evaluation of CD36-Targeting Antiangiogenic Peptide ABT-510 for Near-Infrared Fluorescence Molecular Imaging of Colorectal Cancer.

Surgical resection constitutes the first choice of treatment for colorectal cancer (CRC). Despite advancements in intraoperative navigation, there remains a considerable lack of effective targeting probes for the imaging-guided surgical navigation of CRC owing to their high heterogeneity. Hence, developing a suitable fluorescent probe to detect the specific types of CRC populations is crucial.

In vivo near-infrared fluorescence and SPECT-CT imaging of colorectal Cancer using the bradykinin B2R-specific ligand icatibant.

Cancer molecular imaging using specific probes designed to identify target proteins in cancer is a powerful tool to guide therapeutic selection, patient management, and follow-up. We demonstrated that icatibant may be used as a targeting probe for the significantly upregulated bradykinin B2R in colorectal cancer (CRC). Icatibant-based probes with high affinity towards bradykinin B2R were identified.

In vivo assessing colitis severity by topical administration of fluorescent probe against neutrophils.

Inflammatory bowel disease has become a global burden given its high incidence and refractory to medical treatment. Improved diagnostic strategies to monitor disease activity more accurately are necessary to conduct and evaluate medical treatment. High level of neutrophil infiltration in colon is associated with poor prognosis and enhanced risk of developing colitis-associated cancer.

Detection of colorectal cancer using a small molecular fluorescent probe targeted against c-Met.

Colorectal cancer (CRC), a highly heterogeneous genetic disease, is currently the second leading cause of cancer-related deaths worldwide. This malignant cancer is typically preceded by the development of precancerous lesions, which are challenging to distinguish their subtle morphologic changes. Molecular-based fluorescence imaging can effectively identify lesion targets to enhance image contrast and improve the detection of early neoplasia comparing to conventional wide-light screening endoscopy.

AT1R-Specific Ligand Angiotensin II as a Novel SPECT Agent for Hepatocellular Carcinoma Diagnosis.

Hepatocellular carcinoma (HCC) is characterized by a high mortality and early diagnosis and treatment are critically needed. Ang II type 1 receptor (AT1R) has recently emerged as a potential molecular target for cancer diagnosis and intervention. Here, we labeled angiotensin II (Ang II), an AT1R ligand that is overexpressed in various solid cancers, with the near-infrared fluorescent dye, MPA, and radionuclide technetium-99m, and evaluated its capacity for HCC detection.

GRPR-targeted SPECT imaging using a novel bombesin-based peptide for colorectal cancer detection.

Colorectal cancer (CRC) is the third most common cancer worldwide, and the prognosis of CRC is better with an earlier diagnosis. The presence of the gastrin-releasing peptide receptor (GRPR) has been documented in very high numbers on colorectal cancer cells, which makes it an ideal biomarker for the diagnosis of CRC. Bombesin (BBN) peptide analogs have been extensively investigated for the imaging of human cancers with GRPR overexpression.

A frog-derived bionic peptide with discriminative inhibition of tumors based on integrin αvβ3 identification.

Aureins, natural active peptides extracted from skin secretions of Australian bell frogs, have become a research focus due to the antitumor effects caused by lysing cell membranes. However, clinical translation of Aureins is still limited by non-selective toxicity between normal and cancer cells. Herein, by structure-activity relationship analysis and rational linker design, a dual-function fusion peptide RA3 is designed by tactically fusing Aurein peptide A1 with strong anticancer activity, with a tri-peptide with integrin αvβ3-binding ability which was screened in our previous work.

A novel peptide targeting gastrin releasing peptide receptor for pancreatic neoplasm detection.

Pancreatic cancer has a high mortality rate and efforts towards diagnosis and therapy at an early stage are particularly appealing. Recently, a small peptide, BBN7-14, has attracted much attention for its specific binding ability to gastrin releasing peptide receptor (GRPR), which is highly overexpressed in various types of cancer, including pancreatic cancer. However, its poor stability in vivo restricts its direct clinical application.

Homotypic targeting upconversion nano-reactor for cascade cancer starvation and deep-tissue phototherapy.

Cancer starvation therapy based on catalytic chemistry of glucose oxidase (GOx) offers great potential for multimodal treatment, benefiting from both nutrition shutting-off and the oxidization product hydrogen peroxide (HO). Herein, further optimization of such combined therapy was achieved by a cascade Nano-reactor, which was constructed by incorporating GOx into a bio-mimic upconversion nanosystem. The cascade began when GOx was delivered into tumor sites through homotypic targeting, facilitating selective starving of cancer cells and HO generation.

Discovery of novel quinazoline derivatives bearing semicarbazone moiety as potent EGFR kinase inhibitors.

Aimed at discovering effective EGFR inhibitors, six series of quinazoline derivatives bearing a semicarbazone moiety were designed, synthesized and evaluated in different cancer cell lines (A549, HepG2, MCF-7 and PC-3). Most of the selected compounds showed remarkable cytotoxicity with IC values reaching the nanomole range. Further, the inhibition efficacy of 11 compounds against EGFR kinases was tested, which demonstrated excellent IC values in nanomolar level.

Design, synthesis, and docking studies of quinazoline analogues bearing aryl semicarbazone scaffolds as potent EGFR inhibitors.

Two series of quinazoline derivatives bearing aryl semicarbazone scaffolds (9a-o and 10a-o) were designed, synthesized and evaluated for the IC values against four cancer cell lines (A549, HepG2, MCF-7 and PC-3). The selected compound 9o was further evaluated for the inhibitory activity against EGFR kinases. Four of the compounds showed excellent cytotoxicity activity and selectivity with the IC values in single-digit μM to nanomole range.

Design, synthesis, and docking studies of afatinib analogs bearing cinnamamide moiety as potent EGFR inhibitors.

Two series of afatinib derivatives bearing cinnamamide moiety (10a-n and 11a-h) were designed, synthesized and evaluated for the IC50 values against four cancer cell lines (A549, PC-3, MCF-7 and Hela). Two selected compounds (10e, 10k) were further evaluated for the inhibitory activity against EGFR and VEGFR2/KDR kinases. Seven of the compounds showed excellent cytotoxicity activity and selectivity with the IC50 values in single-digit μM to nanomole range.